Androgenetic Alopecia

Complex MONDO:0005339 Pathograph 49 Show in embeddings browser Skin Disease Hair Disorder Endocrine-Responsive Disorder

Androgenetic alopecia is a common, polygenic disorder of progressive patterned scalp-hair thinning associated with follicular miniaturization. Male-pattern hair loss commonly affects frontotemporal and vertex scalp; female-pattern hair loss commonly causes central thinning with variable frontal accentuation. These distributions overlap between sexes. Local androgen signaling has strong support in male-pattern disease, while the contribution of androgens to female-pattern disease varies and remains incompletely resolved. Clinical severity, rate of change and psychosocial impact differ substantially between individuals.

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Classifications

Harrison's Part

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Mappings

MONDO

MONDO:0007184 alopecia, androgenetic, 1 Not Yet Curated

MONDO:0007184 is the OMIM locus term for androgenetic alopecia 1 (AGA1), the form of common baldness attributed to the androgen-receptor / EDA2R locus on Xq11-q12. It is not a distinct clinical disease: AGA1 is the X-linked susceptibility component of the same patterned, androgen-dependent hair loss that this entry curates, and the AR/EDA2R locus is the strongest single signal in every genome-wide study of the trait (PMID:15902657, PMID:18385763, PMID:28349362). This entry is therefore broader than the locus term, since it also carries the 20p11 signal and the several hundred autosomal loci, so the mapping is recorded as narrowMatch rather than exactMatch. The stub keyed on MONDO:0007184 is retired by this entry.

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Inheritance

Polygenic Inheritance HP:0010982

A polygenic, sex-limited, age-dependent trait rather than a Mendelian disease. Twin studies put the heritability of male pattern baldness near 0.8, pedigree heritability in UK Biobank is 0.62, and several hundred genome-wide significant loci are known. The classic observation that baldness follows the maternal line reflects the strongest single signal, which lies at the androgen receptor / EDA2R locus on the X chromosome and is therefore inherited from the mother; but the X-linked locus accounts for only a minority of the heritable variance and the 20p11 locus and hundreds of autosomal loci are inherited from either parent, so the mode of inheritance is recorded as polygenic, not X-linked.

Polygenic inheritance

Show evidence (4 references)

PMID:30573740 SUPPORT Human Clinical

"Here we show that MPB is strongly heritable and polygenic, with pedigree-heritability of 0.62 (SE = 0.03) estimated from close relatives, and SNP-heritability of 0.39 (SE = 0.01) from conventionally-unrelated males."

The largest single-cohort analysis states the polygenic architecture directly and quantifies heritability from relatives and from SNPs.

PMID:30573740 SUPPORT Human Clinical

"Early twin studies estimated the narrow-sense heritability (h2) on a scale of liability to be 0.817 (95%CI: 0.77–0.85)."

The twin heritability of about 0.8 that the description cites, quoted from the introduction of the same paper because the original twin study (Nyholt 2003, PMID:14675213) has no abstract in PubMed.

PMID:15902657 SUPPORT Human Clinical

"The X-chromosomal location of AR stresses the importance of the maternal line in the inheritance of AGA."

Gives the reason for the classic maternal-line observation without making the trait X-linked: the strongest locus is on the X chromosome.

+ 1 more reference

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Subtypes

Male pattern hair loss (Hamilton-Norwood pattern) MONDO:0800201

Frontotemporal recession and vertex thinning commonly occur in men and are graded with the Hamilton-Norwood scale. The androgen mechanism and evidence for 5-alpha-reductase inhibition are strongest in this presentation. Pattern labels describe distribution rather than excluding a similar pattern in another sex.

Show evidence (2 references)

PMID:1188424 SUPPORT PRIMARY RESULT Human Clinical

"This report establishes such a classification, and reports its use in determining the incidence of male pattern baldness at various ages in 1,000 white adult male subjects."

The Norwood classification and its incidence survey.

PMID:38610726 SUPPORT REVIEW SYNTHESIS Human Clinical

"Typically, hair thinning in the frontotemporal areas, the recession of the frontotemporal hairline and hair loss in the vertex area occur in male androgenetic alopecia (MAGA)."

States the distribution that defines the male pattern.

Female pattern hair loss (Ludwig / Sinclair pattern)

Central and crown thinning with widening of the part commonly occurs in women, including Ludwig-type diffuse thinning, frontal accentuation and less often Hamilton-type recession. The frontal hairline is often preserved but this is not universal. Most affected women have normal circulating androgen concentrations. The degree of androgen dependence is heterogeneous; a null 1-mg finasteride trial in postmenopausal women does not settle all doses or populations, and a small placebo-controlled spironolactone add-on trial is now available.

Show evidence (3 references)

PMID:921894 SUPPORT PRIMARY RESULT Human Clinical

"To facilitate an early diagnosis (desirable in view of the therapeutic possibilities by means of antiandrogens) a classification of the stages of the common form (female type) of androgenetic alopecia in women is presented."

The Ludwig classification that defines the female pattern.

PMID:16382668 SUPPORT REVIEW SYNTHESIS Human Clinical

"Female pattern hair loss (FPHL) is a common hair disorder of the central scalp."

Locates the female pattern on the central scalp.

PMID:11231244 SUPPORT PRIMARY RESULT Human Clinical

"Female androgenetic alopecia is quite common beginning in the late 20s and reaching its peak after 50 years of age."

Age distribution from a survey of 1,006 Caucasian women.

Discussions and Knowledge Gaps

Is female pattern hair loss androgen-dependent at all, and if so through the same dermal papilla mechanism as the male disease?

KNOWLEDGE GAP OPEN aga_fphl_androgen_dependence

Attached to

has_subtypes#Female pattern hair loss pathophysiology#Dihydrotestosterone-Androgen Receptor Signaling

Androgen-related tissue differences and clinical responses do not establish identical mechanisms across all female-pattern populations. Most affected women have normal circulating androgens. The negative 1-mg finasteride trial in postmenopausal women is dose- and population-specific. A 2025 randomized spironolactone add-on pilot now exists, but primary hair-count differences were not significant and the study was small. Larger trials with prespecified endocrine and tissue strata are needed to identify who benefits and whether response is mediated by the same dermal-papilla pathways as in male-pattern disease.

Proposed experiments

Confirmatory stratified antiandrogen trial in female-pattern hair loss

aga_fphl_antiandrogen_rct

A larger trial could use prespecified androgen-status and tissue-expression strata, standardized background therapy and blinded hair-density outcomes to test heterogeneity of response. This would extend, rather than precede, the small 2025 placebo-controlled adjunct trial.

Show evidence (2 references)

PMID:12573818 SUPPORT REVIEW SYNTHESIS Human Clinical

"In contrast to its beneficial effects in men, finasteride did not improve hair growth in postmenopausal women with FPHL."

The null result applies to the tested postmenopausal population and regimen.

PMID:40978669 SUPPORT PRIMARY RESULT Human Clinical

"However, only the P-value of terminal hair counts approached the cutoff of statistical significance (P = .063)."

The primary hair-count comparison was imprecise and not statistically significant.

Do mouse models of hair growth inhibition, including mice treated with dihydrotestosterone and mice overexpressing prostaglandin synthase, model androgenetic alopecia, or only individual mediators of it?

HUMAN MODEL MISMATCH OPEN aga_mouse_model_mismatch

Attached to

pathophysiology#Follicular Miniaturization animal_models#K14-Ptgs2 mouse with altered skin prostanoids animal_models#Topical PGD2 challenge in prostaglandin-receptor knockout mice

The cited mouse interventions isolate selected mechanisms rather than reproduce human polygenic scalp-pattern disease. K14-Ptgs2 alters multiple prostanoids; topical PGD2 requires Gpr44 for hair-length inhibition but does not induce early catagen; injected IL6 is a separate cycle perturbation. Human follicle culture uses terminal face/brow hair, and the stem/progenitor paper demonstrates functional reconstitution with mouse cells, not rescue of patient scalp stem cells. Transfer between systems must preserve these distinctions.

Proposed experiments

Human balding and non-balding scalp xenografts on immunodeficient mice under controlled androgen

aga_humanized_scalp_xenograft

Graft paired frontal and occipital scalp from the same donors onto immunodeficient mice, castrated or supplemented with dihydrotestosterone, and follow terminal-to-vellus ratio and progenitor markers over successive cycles, so that the regional human program is studied in vivo without relying on mouse follicles.

Show evidence (3 references)

PMID:22440736 SUPPORT PRIMARY RESULT Model Organism

"Furthermore, we find that a transgenic mouse, K14-Ptgs2, which targets prostaglandin-endoperoxide synthase 2 expression to the skin, demonstrates elevated levels of PGD(2) in the skin and develops alopecia, follicular miniaturization, and sebaceous gland hyperplasia, which are all hallmarks of human AGA."

The K14-Ptgs2 model changes upstream prostanoid production and develops hair phenotypes; it is not a selective PGD2 manipulation.

PMID:22440736 SUPPORT PRIMARY RESULT Model Organism

"Whereas Ptgds and Ptgdr knockout mice were both susceptible to the inhibition of hair lengthening, Gpr44 null mice were resistant to the inhibitory effect of PGD2"

Topical-challenge resistance establishes Gpr44 dependence in mice, not a human receptor knockout or clinical rescue.

PMID:21881585 SUPPORT PRIMARY RESULT Model Organism

"Moreover, rhIL-6 injection into the hypodermis of mice during anagen caused premature onset of catagen."

The in-vivo cycle intervention is recombinant IL6 injection in mice.

Is perifollicular microinflammation and fibrosis a cause of follicular miniaturization, a cofactor that accelerates it, or a consequence of it?

KNOWLEDGE GAP OPEN aga_microinflammation_cause_or_consequence

Attached to

pathophysiology#Perifollicular Inflammation pathophysiology#Perifollicular Fibrosis

Small and selected biopsy studies show inflammation and sheath remodeling associated with AGA, but do not establish temporal direction or a treatment-responsive causal pathway. In one 44-person minoxidil subset, regrowth was observed in 55% with significant inflammation versus 77% without, not a halving. Scarring fibrosing alopecia in a pattern distribution is an important differential diagnosis rather than proof that all nonscarring AGA inevitably progresses to follicular destruction.

Proposed experiments

Serial biopsies of transitional scalp with follicle-level tracking of infiltrate and terminal-to-vellus status

aga_serial_biopsy_inflammation

Biopsy the same transitional zone at intervals, mapping individual follicular units, to test whether T-cell infiltration and sheath thickening precede the drop in terminal-to-vellus ratio in the same unit or follow it, and whether follicles that miniaturize without infiltrate exist.

Show evidence (2 references)

PMID:12213548 SUPPORT REVIEW SYNTHESIS Human Clinical

"Since the clinical success rate of treatment of AGA with modulators of androgen metabolism or hair growth promoters is limited, sustained microscopic follicular inflammation with connective tissue remodeling, eventually resulting in permanent hair loss, is considered a possible cofactor in the..."

The current status, a possible cofactor, is the gap.

PMID:1390168 SUPPORT PRIMARY RESULT Human Clinical

"The data suggest that progressive fibrosis of the perifollicular sheath occurs in lesions of pattern alopecia, and may begin with T-cell infiltration of follicular stem cell epithelium."

The causal proposal, framed as may, from the histological study.

What does the AR/EDA2R risk haplotype, or any of the several hundred autosomal risk alleles, actually do to the scalp follicle?

KNOWLEDGE GAP OPEN aga_risk_allele_function

Attached to

pathophysiology#Polygenic Susceptibility

Susceptibility signals nominate AR/EDA2R and many autosomal candidates, but the cited association and expression studies do not establish most allele-specific mechanisms. Absence of statistical AR-by-20p11 interaction is not proof of biochemical androgen independence. The 2017 eQTL overlap uses LD-based coincidence in healthy occipital follicles, not formal causal colocalization; pathway enrichments are candidate interpretations. Polygenic scores distinguish selected phenotypic categories but have not established prospective clinical decision benefit across populations.

Proposed experiments

Allele-specific expression and chromatin accessibility of AR and EDA2R in scalp dermal papilla from risk-haplotype carriers

aga_ar_locus_allelic_expression

In dermal papilla cells from frontal and occipital scalp of carriers and non-carriers, measure allele-specific AR and EDA2R expression, map accessible regulatory elements across the linkage block, and edit candidate variants in immortalized balding dermal papilla lines to test which changes receptor level and androgen-induced DKK1, TGFB1 and IL6 output.

Show evidence (2 references)

PMID:18849994 SUPPORT PRIMARY RESULT Human Clinical

"No interaction was detected with the X-chromosomal androgen receptor locus, suggesting that the 20p11 locus has a role in a yet-to-be-identified androgen-independent pathway."

A major locus whose pathway is explicitly unidentified.

PMID:15902657 SUPPORT PRIMARY RESULT Human Clinical

"The investigation of a large number of genetic variants covering the AR locus suggests that a polyglycine-encoding GGN repeat in exon 1 is a plausible candidate for conferring the functional effect."

The functional variant at the strongest locus remains a candidate.

Does follicular SULT1A1 sulfotransferase activity predict the response to topical minoxidil, and could it be used to select patients or to rescue non-responders?

KNOWLEDGE GAP OPEN aga_sult1a1_minoxidil_response

Attached to

treatments#Topical minoxidil

Follicular sulfotransferase activity is a candidate minoxidil-response biomarker. A 2015 study prospectively assayed 15 participants before topical treatment and reported 100% sensitivity and 71% specificity against a later photographic response classification. Its combined 70-person calculation gave a 95.9% negative predictive value assuming a 40% response prevalence. This is not universal test accuracy, an allele-specific loss-of-function result or evidence that assay-guided prescribing improves outcomes. Broader external validation and prospective clinical utility remain unresolved.

Proposed experiments

External validation and clinical-utility trial of follicular sulfotransferase testing

aga_sult1a1_stratified_minoxidil_trial

Use an independent cohort and prespecified threshold to test calibration across populations, then compare assay-guided care with usual care. Genotype effects should be measured separately rather than inferred from enzymatic activity.

Show evidence (2 references)

url:https://prtimes.jp/a/?f=d59603-106-d6c9c40ba4f09ed7d1658c32d4f991e5.pdf SUPPORT PRIMARY RESULT Human Clinical

"A total of 15 patients (eight male, seven female) were included in our analysis of minoxidil response testing."

The small prospective study updates the previous incorrect claim that no prospective validation existed.

url:https://prtimes.jp/a/?f=d59603-106-d6c9c40ba4f09ed7d1658c32d4f991e5.pdf SUPPORT PRIMARY RESULT Human Clinical

"sensitivity of 100% and a speciﬁcity of 71% (Student’s t-test p < 0.005)."

Performance is estimated in the small prospective subset; no clinical-utility trial follows.

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Pathophysiology

Polygenic Susceptibility

Common variants at the AR/EDA2R region and many autosomal loci are associated with male-pattern hair loss. The largest cited study analyzes self-reported severity in European men, and its conditional analysis ultimately retains 622 association signals. Candidate-gene mapping and pathway enrichment do not establish the molecular action of each allele, and male cohorts do not establish an identical architecture for female-pattern hair loss. The AR locus motivates an androgen-response hypothesis; other susceptibility routes remain unresolved.

AR hgnc:644 EDA2R hgnc:17756 WNT10A hgnc:13829 FGF5 hgnc:3683 TWIST1 hgnc:12428

Downstream

Regional Androgen Receptor Abundance Regulatory variation near AR is proposed to influence scalp receptor abundance, but the association studies do not establish allele-specific mediation.

Follicular Miniaturization Genetic susceptibility is associated with the clinical trait whose tissue hallmark is miniaturization; most intervening allele-to-follicle mechanisms remain untested.

Show evidence (2 references)

PMID:28272467 SUPPORT PRIMARY RESULT Human Clinical

"The 63 loci explain ∼39% of the phenotypic variance in MPB and highlight several plausible candidate genes (FGF5, IRF4, DKK2) and pathways (melatonin signalling, adipogenesis) that are likely to be implicated in the key-pathophysiological features of MPB and may represent promising targets for..."

The European early-onset case-control meta-analysis identifies susceptibility loci; its reported variance is a binary regression estimate, not universal penetrance.

PMID:30573740 SUPPORT PRIMARY RESULT Human Clinical

"Ultimately, the net product was 622 loci: 598 autosomal and 24 on the X-chromosome"

The final conditional signal set is statistical and does not identify 622 experimentally established causal genes.

Regional Androgen Receptor Abundance

Frontal follicles contained more androgen receptor than occipital follicles in a small paired study, with lower frontal abundance in women than men. Cultured dermal papilla cells from balding scalp also had higher receptor binding capacity than non-balding cells. These observations support regional sensitivity but do not prove a universal explanation of sex-specific patterns. Receptor localization is preparation-dependent; the evidence does not justify excluding androgen receptors from all follicular epithelium.

AR hgnc:644

scalp UBERON:0000403 hair follicle UBERON:0002073

Downstream

Dihydrotestosterone-Androgen Receptor Signaling Greater receptor availability may increase ligand-dependent signaling; ligand concentration, receptor occupancy and transcriptional context also contribute.

Show evidence (2 references)

PMID:9284093 SUPPORT PRIMARY RESULT Human Clinical

"Findings revealed that both women and men have higher levels of receptors and 5alpha-reductase type I and II in frontal hair follices than in occipital follicles, whereas higher levels of aromatase were found in their occipital follicles."

Paired frontal/occipital follicle measurements in 12 women and 12 men establish regional abundance differences, not receptor absence elsewhere.

PMID:9496234 SUPPORT PRIMARY RESULT In Vitro

"Balding cells contained significantly (P < 0.01) greater levels of androgen receptors (Bmax = 0.06 +/- 0.01 fmol/10(4) cells (mean +/- S.E.M.)) than those from non-balding scalp (0.04 +/- 0.001)."

Cultured dermal papilla cells retain androgen binding at both sites, with greater binding capacity in balding-derived cells.

Regional 5-Alpha-Reductase Abundance

The paired follicle study found higher type 1 and type 2 5-alpha-reductase levels in frontal than occipital samples from women and men. Higher occipital aromatase and sex-related differences were also reported. These are regional measurements in selected participants, not evidence that all unaffected follicles lack androgen metabolism.

SRD5A2 hgnc:11285 SRD5A1 hgnc:11284

hair follicle UBERON:0002073

Downstream

Local Dihydrotestosterone Production Regional enzyme abundance can alter conversion capacity through enzyme activity, but abundance alone does not quantify net DHT flux or clearance.

Show evidence (1 reference)

PMID:9284093 SUPPORT PRIMARY RESULT Human Clinical

The study measures regional enzyme abundance, not a direct in-vivo steroid flux assay.

Local Dihydrotestosterone Production

5-alpha-reductases convert testosterone to the more potent androgen dihydrotestosterone within the follicular environment. Dermal papilla metabolism is implicated, while type 2 enzyme is also described in outer root sheath tissue. Human endocrine observations and DHT-lowering treatment support an important role in male-pattern disease. Normal circulating androgen concentrations can coexist with local susceptibility; this does not imply every patient has the same steroid profile.

SRD5A2 hgnc:11285 SRD5A1 hgnc:11284

androgen metabolic process GO:0008209 ↑ INCREASED

3-oxo-5-alpha-steroid 4-dehydrogenase activity GO:0003865 ↑ INCREASED

hair follicle UBERON:0002073 dermal papilla UBERON:0000412

Downstream

Dihydrotestosterone-Androgen Receptor Signaling Locally available DHT binds the androgen receptor. This ligand-receptor step is direct; downstream follicular responses depend on cell context.

Show evidence (2 references)

PMID:12213548 SUPPORT REVIEW SYNTHESIS Human Clinical

"Conversion of testosterone to DHT within the dermal papilla plays a central role, while androgen-regulated factors deriving from dermal papilla cells are believed to influence growth of other components of the hair follicle."

The review places local conversion in the follicular androgen mechanism; it is not a direct flux measurement in every follicular compartment.

PMID:12573818 SUPPORT REVIEW SYNTHESIS Human Clinical

"Observations in both eunuchs, who have low levels of testicular androgens, and males with genetic 5alpha-reductase (5alphaR) deficiency, who have low levels of dihydrotestosterone (DHT), implicate DHT as a key androgen in the pathogenesis of MPHL in men."

Human endocrine observations support the importance of DHT in male-pattern hair loss without establishing a universal female mechanism.

Dihydrotestosterone-Androgen Receptor Signaling

Androgen-responsive dermal papilla cells can relay growth-inhibitory signals to follicular keratinocytes. Human coculture evidence includes an AR-transfected preparation that restored responsiveness lost during culture; macaque coculture shows antagonist-sensitive inhibition. These experiments support a paracrine route while leaving its quantitative contribution in patients unresolved. Androgens stimulate growth at other body sites, so signaling consequences depend on follicular context.

hair follicle dermal papilla cell of scalp CL:2000083

AR hgnc:644

androgen receptor signaling pathway GO:0030521 ↑ INCREASED

dermal papilla UBERON:0000412

Experimental models

Macaque dermal-papilla and outer-root-sheath coculture CO CULTURE Testosterone and an AR blocker probe androgen-dependent epithelial inhibition mediated by dermal papilla cells.

Downstream

Increased TGF-Beta1 Secretion Androgen exposure increases TGF-beta1 secretion in the AR-transfected dermal papilla preparation; the intervening regulatory steps are not resolved.

Increased DKK1 Secretion DHT induces DKK1 expression and secretion in culture; the full receptor-to-transcription mechanism is not mapped by the cited assay.

Increased IL6 Secretion DHT induces IL6 secretion in cultured balding-derived dermal papilla cells; this is not proof of obligatory cytokine mediation in patients.

Reduced Canonical Wnt Signaling in Dermal Papilla Cells Androgen treatment alters the measured Wnt pathway readouts in dermal papilla cells; the intervening molecular interaction is unresolved.

Show evidence (2 references)

PMID:12397096 SUPPORT PRIMARY RESULT In Vitro

"In this modified coculture, androgen significantly suppressed the growth of KCs by approximately 50%, indicating that overexpression of AR can restore the responsiveness of the DPCs to androgen in vivo."

Androgen inhibition required AR-transfected human dermal papilla cells in this assay; native cultured cells initially lacked a significant response.

PMID:8977424 SUPPORT PRIMARY RESULT In Vitro

"Furthermore, RU 58841, an androgen receptor blocker, antagonized this testosterone-elicited inhibition."

An AR blocker antagonized testosterone-dependent inhibition in macaque dermal-papilla/outer-root-sheath coculture.

Increased TGF-Beta1 Secretion

Androgen exposure increased TGF-beta1 secretion in AR-transfected human dermal papilla cells. Neutralizing TGF-beta1 reversed growth inhibition of cocultured keratinocytes, supporting mediation within this preparation. The experiment does not establish that every untreated patient follicle uses this route to the same extent.

hair follicle dermal papilla cell of scalp CL:2000083

TGFB1 hgnc:11766

transforming growth factor beta1 production GO:0032905 ↑ INCREASED

Experimental models

AR-transfected human dermal-papilla and keratinocyte coculture CO CULTURE Androgen exposure tests secreted TGF-beta1 in the modified coculture.

Downstream

Reduced Follicular Keratinocyte Proliferation TGF-beta1-dependent signaling mediates growth suppression in the modified coculture; receptor signaling and cell-cycle control intervene between secretion and the population readout.

Show evidence (1 reference)

PMID:12397096 SUPPORT PRIMARY RESULT In Vitro

"ELISA assays demonstrated that androgen treatment increased the secretion of both total and active TGF-beta1 in the conditioned medium."

Androgen increased secreted TGF-beta1 in AR-transfected dermal papilla culture.

Increased DKK1 Secretion

DHT increased DKK1 expression and secretion in human dermal papilla cultures. DKK1 protein was also higher in bald than haired patient scalp. Neutralization and recombinant-protein experiments support keratinocyte growth inhibition and apoptosis in vitro; the paired scalp observation alone does not establish causality.

hair follicle dermal papilla cell of scalp CL:2000083

DKK1 hgnc:2891

Downstream

Reduced Follicular Keratinocyte Proliferation DKK1 neutralization reverses DHT-associated outer-root-sheath growth inhibition in coculture; the full route from secreted antagonist to cell-number change is not mapped.

Increased Follicular Keratinocyte Apoptosis Recombinant DKK1 induces apoptosis in cultured outer-root-sheath cells. The experiment does not isolate every intracellular intermediate.

Show evidence (2 references)

PMID:17657240 SUPPORT PRIMARY RESULT In Vitro

"DKK-1 messenger RNA is upregulated in 3-6 hours after 50-100 nM DHT treatment and ELISA showed that DKK-1 is secreted from DP cells in response to DHT."

DHT exposure increased DKK1 transcript and secreted protein in cultured human dermal papilla cells.

PMID:17657240 SUPPORT PRIMARY RESULT Human Clinical

"Moreover, immunoblotting showed that the DKK-1 level is up in the bald scalp compared with the haired scalp of patients with androgenetic alopecia."

Patient scalp immunoblotting is an observational comparison distinct from the culture perturbations.

Increased IL6 Secretion

DHT increased IL6 secretion in balding-derived dermal papilla cultures. Recombinant IL6 suppressed matrix-cell proliferation and shaft elongation in human follicle organ culture; injection during mouse anagen induced early catagen. Human organ culture and mouse cycle effects are distinct findings, not a demonstrated universal patient sequence.

hair follicle dermal papilla cell of scalp CL:2000083

IL6 hgnc:6018

interleukin-6 production GO:0032635 ↑ INCREASED

Downstream

Reduced Follicular Keratinocyte Proliferation IL6 receptor signaling and downstream cell-cycle regulation connect recombinant cytokine exposure to reduced matrix proliferation in organ culture.

Shortened Anagen Injected recombinant IL6 induces premature catagen in mice. Its contribution to shortened anagen in human AGA remains an experimental extrapolation.

Show evidence (1 reference)

PMID:21881585 SUPPORT PRIMARY RESULT In Vitro

"IL-6 was upregulated 3 hours after 10-100 nM DHT treatment, and ELISA showed that IL-6 was secreted from balding DP cells in response to DHT."

DHT exposure increased IL6 expression and secretion in balding-derived dermal papilla cultures.

Reduced Canonical Wnt Signaling in Dermal Papilla Cells

Androgen-treated dermal papilla cells showed a lower cytoplasmic-to-total beta-catenin ratio and increased GSK3beta activity, interpreted as canonical Wnt inhibition. Wnt activation restored their ability to induce keratin expression in cocultured follicular cells. The measured signaling compartment is dermal papilla; this is separate from the reduced marker-defined progenitor populations observed in patient scalp.

hair follicle dermal papilla cell of scalp CL:2000083

canonical Wnt signaling pathway GO:0060070 ↓ DECREASED

Experimental models

Human dermal-papilla Wnt and differentiation coculture CO CULTURE Androgen treatment alters the measured pathway state.

Downstream

Impaired Follicular Epithelial Differentiation The rescue supports a Wnt-dependent contribution to dermal-papilla induction of epithelial differentiation; the complete paracrine relay is unresolved.

Show evidence (1 reference)

PMID:22283397 SUPPORT PRIMARY RESULT In Vitro

"Androgen treatment revealed a significant decrease in the cytoplasmic/total β-catenin protein ratio and upregulation of the activity of glycogen synthase kinase-3β in DPC, indicative of canonical Wnt pathway inhibition."

The beta-catenin and GSK3beta measurements were in dermal papilla cells, not the follicular epithelium.

Impaired Follicular Epithelial Differentiation

Androgen-treated dermal papilla cells had reduced ability to induce hair keratin expression in cocultured follicular stem-cell preparations, restored by Wnt activation. This differentiation readout does not demonstrate a lineage-conversion block in living patient follicles.

hair follicular keratinocyte CL:2000092

hair follicle UBERON:0002073

Experimental models

Human dermal-papilla Wnt and differentiation coculture CO CULTURE Hair keratin induction is used as a differentiation readout.

Downstream

Follicular Miniaturization Reduced epithelial differentiation is a candidate contributor to diminished follicle output, but culture rescue does not establish the complete mechanism of patient miniaturization.

Show evidence (1 reference)

PMID:22283397 SUPPORT PRIMARY RESULT In Vitro

"Wnt signalling activation restored the ability of androgen-treated DPC to induce differentiation."

Wnt activation rescues the differentiation-inducing activity of androgen-treated dermal papilla cells in coculture.

Reduced Follicular Keratinocyte Proliferation

TGF-beta1-dependent coculture inhibition and recombinant IL6 effects support reduced epithelial growth in experimental follicular systems. These assays use different cell preparations and do not establish a single obligatory inhibitory cocktail in patients.

hair follicular keratinocyte CL:2000092

hair follicle cell proliferation GO:0071335 ↓ DECREASED

Experimental models

AR-transfected human dermal-papilla and keratinocyte coculture CO CULTURE Neutralizing TGF-beta1 reverses the coculture growth inhibition.

Downstream

Follicular Miniaturization Reduced epithelial growth could limit follicular output; the experiments do not show that this readout alone produces the chronic human tissue phenotype.

Show evidence (2 references)

PMID:12397096 SUPPORT PRIMARY RESULT In Vitro

"Moreover, the neutralizing anti-TGF-beta1 antibody reversed the androgen-elicited growth inhibition of KCs in a dose-dependent manner."

Growth inhibition is measured in the AR-transfected dermal-papilla/keratinocyte preparation.

PMID:21881585 SUPPORT PRIMARY RESULT In Vitro

"Recombinant human IL-6 (rhIL-6) inhibited hair shaft elongation and suppressed proliferation of matrix cells in cultured human hair follicles."

Recombinant cytokine suppresses matrix proliferation and elongation in human follicle culture.

Increased Follicular Keratinocyte Apoptosis

Recombinant DKK1 induced outer-root-sheath keratinocyte apoptosis, and DKK1 neutralization countered DHT-associated cell death in cultured follicles. This provides an experimental epithelial-injury route; it does not demonstrate loss of the KRT15-defined human bulge compartment.

outer root sheath cell CL:0002561

keratinocyte apoptotic process GO:0097283 ↑ INCREASED

Downstream

Follicular Miniaturization Experimental epithelial apoptosis may contribute to reduced follicle output, but its necessity and quantitative role in patient miniaturization are unresolved.

Show evidence (1 reference)

PMID:17657240 SUPPORT PRIMARY RESULT In Vitro

"Also, recombinant human DKK-1 inhibited the growth of ORS cells and triggered apoptotic cell death."

Recombinant DKK1 induces apoptosis in cultured outer-root-sheath cells; this is not a patient lineage-depletion measurement.

Prostaglandin D2 Elevation in Bald Scalp

PTGDS expression and PGD2 were elevated in bald compared with haired scalp from selected male hair-transplant donors. The patient observations are cross-sectional. An androgen-to-PTGDS bridge in human scalp was not directly tested, and the multiple-prostanoid K14-Ptgs2 mouse does not establish selective PGD2 sufficiency.

PTGDS hgnc:9592

scalp UBERON:0000403

Animal models

K14-Ptgs2 mouse with altered skin prostanoids Mouse perturbs Upstream cyclooxygenase overexpression increases skin PGD2.

Downstream

PGD2-Associated Hair Growth Inhibition Elevated tissue PGD2 motivates a receptor-mediated inhibitory route supported by organ culture and mouse perturbation, but the human concentration-response and receptor-necessity bridge remain unproven.

Show evidence (1 reference)

PMID:22440736 SUPPORT PRIMARY RESULT Human Clinical

"We show that prostaglandin D(2) synthase (PTGDS) is elevated at the mRNA and protein levels in bald scalp compared to haired scalp of men with AGA."

Paired scalp measurements show elevated synthase expression in selected male transplant patients.

PGD2-Associated Hair Growth Inhibition

PGD2 inhibited elongation of terminal human face/brow follicles in organ culture and hair lengthening after topical mouse exposure. Gpr44-null mice resisted the topical effect, whereas Ptgdr-null mice remained sensitive. Human receptor involvement was inferred from agonist correlations. Topical PGD2 did not elicit premature mouse catagen, so growth inhibition is not equated with an established regression or miniaturization sequence.

hair follicle UBERON:0002073

Experimental models

Human terminal follicle organ culture exposed to PGD2 OTHER Exogenous prostaglandin exposure reduces cultured hair elongation.

Animal models

Topical PGD2 challenge in prostaglandin-receptor knockout mice Mouse perturbs The genotype comparison tests Gpr44 dependence of the topical response.

Downstream

Patterned non-scarring scalp hair loss Experimental inhibition of hair output is a plausible contributor to visible thinning, but no intervention in this study establishes PGD2-mediated clinical hair loss or regrowth in patients.

Show evidence (2 references)

PMID:22440736 SUPPORT PRIMARY RESULT In Vitro

"We show that PGD(2) inhibits hair growth in explanted human hair follicles and when applied topically to mice."

The paper includes growth inhibition of explanted human follicles; mouse topical experiments are assessed separately.

PMID:22440736 SUPPORT PRIMARY RESULT Model Organism

"Whereas Ptgds and Ptgdr knockout mice were both susceptible to the inhibition of hair lengthening, Gpr44 null mice were resistant to the inhibitory effect of PGD2"

Topical-challenge resistance establishes Gpr44 dependence in mice, not a human receptor knockout or clinical rescue.

Reduced Marker-Defined Follicular Progenitor Compartments

Paired bald frontal and haired occipital scalp showed lower CD200-high/ITGA6-high and CD34-high cell proportions, while KRT15-high proportions were similar. Assay subsets were small: eight paired KRT15 comparisons, nine CD200/ITGA6 comparisons and three CD34 comparisons. Preserved marker fractions do not establish normal absolute stem-cell numbers or regenerative function. A stem-to-progenitor conversion defect is inferred, and the source explicitly leaves primary versus secondary causation unresolved.

hair follicular keratinocyte CL:2000092

hair follicle bulge UBERON:0005975

Downstream

Follicular Miniaturization Reduced progenitor compartments could limit epithelial renewal, but the paired observational study does not establish temporal direction or a necessary conversion block.

Show evidence (3 references)

PMID:21206086 SUPPORT PRIMARY RESULT Human Clinical

"On average, the percentage of KRT15hicells was the same in bald and haired scalp"

The paired KRT15 assay measures similar cell proportions, not absolute normal stem-cell numbers or functional rescue.

PMID:21206086 SUPPORT PRIMARY RESULT Human Clinical

"These findings support the notion that a defect in conversion of hair follicle stem cells to progenitor cells plays a role in the pathogenesis of AGA."

Cross-sectional marker differences motivate a conversion hypothesis; human lineage tracing and conversion-rate measurements were not performed.

PMID:21206086 SUPPORT PRIMARY RESULT Human Clinical

"Whether the decrease in these cells is a primary or secondary event in AGA remains to be determined"

The study explicitly limits the causal interpretation of reduced progenitor-marker populations.

Premature Senescence of Cultured Dermal Papilla Cells

Balding-derived dermal papilla cultures displayed slower growth and senescence-associated morphology, beta-galactosidase and p16/pRB changes. This is a culture phenotype and a proposed contributor to reduced regenerative capacity; the study does not establish androgen-triggered senescence or dermal-papilla depletion in living patients.

hair follicle dermal papilla cell of scalp CL:2000083

cellular senescence GO:0090398 ↑ INCREASED

Downstream

Follicular Miniaturization A reduced ability of dermal papilla cells to maintain their population is a proposed route to smaller follicles; in-vivo mediation remains untested.

Show evidence (1 reference)

PMID:17989730 SUPPORT PRIMARY RESULT In Vitro

"Premature senescence of balding DPC in vitro in association with expression of p16(INK4a)/pRB suggests that balding DPC are sensitive to environmental stress and identifies alternative pathways that could lead to novel therapeutic strategies for treatment of AGA."

The senescence phenotype is measured in cultured balding-derived dermal papilla cells, with no demonstrated in-vivo cell-loss sequence.

Shortened Anagen

AGA is associated with a shorter active hair-growth phase and an altered anagen-to-telogen balance. Less time in anagen can limit shaft length and the number of actively growing hairs. Shortened cycling alone is not sufficient to explain all observed miniaturization, and no obligatory anagen-to-miniaturization edge is asserted.

hair follicle UBERON:0002073

Animal models

Recombinant IL6 injection during mouse anagen Mouse perturbs The induced early catagen endpoint shortens the active-growth interval.

Downstream

Fine, short vellus-like scalp hairs Reduced time for shaft growth contributes to short hairs; shaft caliber additionally depends on follicle size.

Patterned non-scarring scalp hair loss A smaller fraction of actively growing follicles can reduce visible hair coverage through altered cycle occupancy.

Show evidence (1 reference)

PMID:41606541 SUPPORT REVIEW SYNTHESIS Human Clinical

"Androgenetic alopecia (AGA), the most prevalent type of hair loss, is characterized by progressive hair follicle miniaturization and disruption of the hair growth cycle, with a shortened anagen phase and an extended telogen phase, eventually leading to baldness [1]."

The review describes the clinical hair-cycle phenotype; this sentence is background synthesis, not a new longitudinal cycle experiment.

Prolonged Kenogen

A longer interval between shedding and renewed anagen growth may leave more follicles temporarily empty. This hair-cycle contribution to reduced density is distinct from a reduction in follicle size and is not quantified for all patients.

hair follicle UBERON:0002073

Downstream

Patterned non-scarring scalp hair loss Longer empty intervals reduce the number of visible shafts at a given time, without requiring permanent follicle loss.

Show evidence (1 reference)

PMID:38610726 SUPPORT REVIEW SYNTHESIS Human Clinical

"The reduction in hair density may also be attributed to the extension of the kenogen phase, occurring concurrently with the miniaturization process of the hair follicle in the frontoparietal region [4]."

The review proposes longer empty-follicle intervals as an additional contributor to reduced density.

Follicular Miniaturization

Affected scalp contains smaller follicles producing finer, shorter shafts, with fewer terminal hairs and increased vellus-like hairs and fibrous streamers. Miniaturization is a tissue hallmark of nonscarring AGA. A reduction in dermal-papilla cell number has been proposed as a mediator, but is not established by the cited conceptual paper. Perifollicular fibrosis and distinct scarring alopecias must not be treated as inevitable progression of this process.

hair follicle cell CL:0002559

hair follicle UBERON:0002073

Animal models

Stump-tailed macaque spontaneous frontal balding Macaca arctoides partially recapitulates The model displays age-related follicular regression and growth responses under DHT-lowering treatment.

K14-Ptgs2 mouse with altered skin prostanoids Mouse partially recapitulates Miniaturization and alopecia accompany altered skin prostanoid production.

Downstream

Patterned non-scarring scalp hair loss Smaller follicles produce fine shafts and reduced visible coverage; the distribution reflects which scalp regions are affected.

Fine, short vellus-like scalp hairs Smaller follicles produce fine shafts and reduced visible coverage; the distribution reflects which scalp regions are affected.

Hair diameter variability on trichoscopy Smaller follicles produce fine shafts and reduced visible coverage; the distribution reflects which scalp regions are affected.

Frontotemporal hairline recession and vertex thinning Regional follicular susceptibility determines the distribution of miniaturization. These clinical patterns overlap between sexes rather than defining exclusive mechanisms.

Diffuse central scalp thinning with preserved frontal hairline Regional follicular susceptibility determines the distribution of miniaturization. These clinical patterns overlap between sexes rather than defining exclusive mechanisms.

Show evidence (2 references)

PMID:8496421 SUPPORT PRIMARY RESULT Human Clinical

"The diagnosis of MPAA was confirmed by finding decreased terminal hairs and increased stelae and vellus hairs."

Horizontal biopsy sections show fewer terminal hairs and more vellus hairs and stelae in a selected male-pattern series.

PMID:11511857 SUPPORT REVIEW SYNTHESIS Human Clinical

"It is hypothesized that the miniaturization seen with pattern hair loss may be the direct result of reduction in the cell number and, hence, size of the dermal papilla."

The source explicitly presents papilla cell-number reduction as a hypothesis.

Perifollicular Inflammation

Activated T cells, mast-cell degranulation and fibroblast activation were described around follicles in a small progressive-pattern biopsy series. Larger biopsy data associate inflammation with a lower observed minoxidil response. These cross-sectional findings do not determine whether inflammation precedes, follows or independently modifies miniaturization.

T cell CL:0000084 mast cell CL:0000097

inflammatory response GO:0006954 ↑ INCREASED

hair follicle UBERON:0002073

Downstream

Perifollicular Fibrosis Inflammation may contribute to connective-tissue remodeling, but the biopsy associations do not isolate an inflammatory-to-fibrotic sequence.

Peripilar sign on trichoscopy Peripilar discoloration is associated with superficial perifollicular inflammation in trichoscopic literature, but is not a universal or individually definitive inflammatory marker.

Show evidence (2 references)

PMID:1390168 SUPPORT PRIMARY RESULT Human Clinical

"Immunohistochemically, control biopsies were devoid of follicular inflammation (n = 3), while transitional regions consistently showed the presence of activated T-cell infiltrates about the lower portions of follicular infundibula."

Activated T-cell infiltration was observed in transitional scalp from three men and one woman, with three controls; it is not a universal AGA finding.

PMID:8496421 SUPPORT PRIMARY RESULT Human Clinical

"In MPAA with no significant inflammation, regrowth occurred in 77% of cases, versus 55% in cases with significant inflammation."

In a 44-person treatment subset, observed regrowth was 77% without versus 55% with significant inflammation; this is not a randomized inflammatory intervention.

Perifollicular Fibrosis

Perifollicular sheath thickening and fibrosis can accompany AGA. Connective-tissue remodeling is a proposed modifier of follicular function, with unresolved causal direction. Follicular dropout in fibrosing alopecia in a pattern distribution represents a scarring differential diagnosis and is not established as the inevitable endpoint of nonscarring AGA.

fibroblast CL:0000057

extracellular matrix organization GO:0030198 ↑ INCREASED

hair follicle UBERON:0002073

Downstream

Follicular Miniaturization Sheath remodeling may impair normal cycling or follicular support, but its direction and necessity in AGA remain unresolved.

Show evidence (2 references)

PMID:1390168 SUPPORT PRIMARY RESULT Human Clinical

"This finding was associated with mast cell degranulation and fibroblast activation within the fibrous sheaths."

Mast-cell degranulation and fibroblast activation accompany sheath changes; temporal causation was not tested.

PMID:12213548 SUPPORT REVIEW SYNTHESIS Human Clinical

The review describes inflammation and remodeling as a possible cofactor, not an established obligatory cause.

✶

Histopathology

Reduced terminal-to-vellus hair ratio with fibrous streamers

Horizontal sections permit terminal and vellus follicle counts and show miniaturization with increased fibrous streamers. In a series of 106 male-pattern cases and 22 controls, the affected-sample average terminal-to-vellus ratio was 1.7:1, and horizontal counts met the study diagnostic ratio in 67% of cases. These are study-specific observations, not universal diagnostic sensitivity. The diagnostic S1 guideline recommends considering both horizontal and vertical sections when biopsy is required, particularly to distinguish scarring or diffuse inflammatory disorders.

Show evidence (3 references)

PMID:8496421 SUPPORT PRIMARY RESULT Human Clinical

"The average horizontal section contained 22 terminal and 13 vellus hairs, a 1.7:1 ratio."

The measured terminal-to-vellus ratio in affected men.

PMID:8496421 SUPPORT PRIMARY RESULT Human Clinical

"Changes compatible with MPAA were found in most vertical and horizontal sections, but horizontal sections were required for follicular counts and showed terminal:vellus hair ratios diagnostic of MPAA in 67% of cases."

Diagnostic yield of horizontal sectioning.

PMID:15787815 SUPPORT PRIMARY RESULT Human Clinical

"80 women aged between 12 and 79 years, with FPHL and biopsy-confirmed hair follicle miniaturization"

Biopsy-confirmed miniaturization was the entry criterion in the female series; the source's bracketed threshold (terminal to vellus ratio of 4 to 1 or below) cannot be quoted through the validator's bracket stripping and is described in the prose only.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

Head and Neck 1

Diffuse central scalp thinning with preserved frontal hairline Sparse scalp hair HP:0002209

Show evidence (2 references)

PMID:38610726 SUPPORT REVIEW SYNTHESIS Human Clinical

"In female androgenetic alopecia (FAGA), hair thinning occurs over the frontal and parietal areas of the scalp (Ludwig type)"

The female distribution.

PMID:921894 SUPPORT PRIMARY RESULT Human Clinical

"The exceptionally observed male type of androgenetic alopecia can be classified according to Hamilton or to the modification of this classification proposed by Ebling & Rook."

The male-type pattern is the exception in women, so the Ludwig pattern is the rule.

Integument 3

Patterned non-scarring scalp hair loss OBLIGATE Alopecia HP:0001596

Show evidence (2 references)

PMID:12213548 SUPPORT REVIEW SYNTHESIS Human Clinical

"Androgenetic alopecia (AGA) is hereditary and androgen-dependent, progressive thinning of the scalp hair that follows a defined pattern."

The defining description; obligate because it is the definition.

PMID:38610726 SUPPORT REVIEW SYNTHESIS Human Clinical

"Androgenetic alopecia (AGA), also known as pattern hair loss, is the most common cause of non-scarring alopecia."

Non-scarring, and the most common cause of it.

Frontotemporal hairline recession and vertex thinning Frontal balding HP:0002292

Show evidence (3 references)

PMID:38610726 SUPPORT REVIEW SYNTHESIS Human Clinical

"Typically, hair thinning in the frontotemporal areas, the recession of the frontotemporal hairline and hair loss in the vertex area occur in male androgenetic alopecia (MAGA)."

The male distribution.

PMID:30573740 SUPPORT PRIMARY RESULT Human Clinical

"The balding process is highly patterned, suggesting that MPB progression is induced by some ageing-associated program: from initial frontotemporal hairline recession to a more severe occipital horseshoe stage1."

The progression from recession to the horseshoe stage.

PMID:9865198 SUPPORT PRIMARY RESULT Human Clinical

"Twelve percent of the men were classified as having predominantly frontal baldness (type A variants)."

Frequency of the frontal-predominant variant in a community sample.

Fine, short vellus-like scalp hairs Fine hair HP:0002213

Show evidence (2 references)

PMID:11511857 SUPPORT PRIMARY RESULT Human Clinical

"In androgenetic alopecia, or pattern hair loss, follicles undergo miniaturization, shrinking from terminal to vellus-like hairs."

The terminal-to-vellus conversion that produces the fine hair.

PMID:38610726 SUPPORT REVIEW SYNTHESIS Human Clinical

"The most common features identified using trichoscopy included hair diameter variability (94.07% of patients), vellus hairs (66.45%) and the peripilar sign (43.27%)."

Vellus hairs in 66.45% of patients across 34 studies, which places the frequency in the FREQUENT band.

Metabolism 1

Insulin resistance (associated) HP:0000855

Show evidence (3 references)

PMID:41606541 SUPPORT PRIMARY RESULT Human Clinical

"A paternal family history of AGA (OR 2.22, 95% CI 1.59–3.10), insulin resistance (standardized mean difference [SMD] 0.40, 95% CI 0.27–0.53), and high fasting insulin levels (SMD 0.48, 95% CI 0.18–0.78) were also identified as factors that increased the risk of the presence of AGA."

Pooled insulin resistance and fasting insulin differences.

PMID:20426781 SUPPORT PRIMARY RESULT Human Clinical

"A statistically significant association was found between AGA and the presence of metabolic syndrome [odds ratio (OR) 1.67, 95% confidence interval (CI) 1.01-2.74] as well as between AGA and the number of fulfilled metabolic syndrome components (OR 1.21, 95% CI 1.03-1.42) after controlling for..."

The community-based association with metabolic syndrome, adjusted for confounders.

PMID:20619491 SUPPORT PRIMARY RESULT Human Clinical

"Metabolic syndrome was diagnosed in 60% of male patients with AGA (odds ratio [OR] = 10.5, 95% confidence interval [CI] 3.3-32.5), 48.6% of female patients with AGA (OR = 10.73, 95% CI 2.7-41.2), 12.5% of male control subjects, and 8.1% of female control subjects (P < .0001)."

The early-onset case-control finding in both sexes.

Nervous System 1

Anxiety associated with hair loss HP:0000739

Show evidence (3 references)

PMID:41606541 SUPPORT BACKGROUND Human Clinical

"The appearance of hair loss can impose a significant psychological burden on patients, leading to anxiety, low self-esteem, and severe impairment of personal life and social interaction [2]."

The introduction summarizes reported human psychosocial burden rather than a newly measured outcome in this meta-analysis.

PMID:12196747 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"Additionally, data from a patient questionnaire on quality of life, global benefit, hair growth, and hair styling demonstrated that 5% topical minoxidil helped improve patients' psychosocial perceptions of hair loss."

Treatment improved psychosocial perceptions in a trial population, which implies the perceptions were impaired; indirect because it is a treatment-response inference.

PMID:39192534 SUPPORT PRIMARY RESULT Human Clinical

"There was no significant association between the presence of AGA or its severity with depression, anxiety, quality of life, self-esteem or sexual symptoms."

The selected birth-cohort follow-up did not find an association at this age; this qualifies generalization rather than refuting distress in every patient.

Other 2

Hair diameter variability on trichoscopy

Show evidence (2 references)

PMID:38610726 SUPPORT REVIEW SYNTHESIS Human Clinical

"The most common features identified using trichoscopy included hair diameter variability (94.07% of patients), vellus hairs (66.45%) and the peripilar sign (43.27%)."

Pooled frequencies, 94.07% for diameter variability, in the VERY_FREQUENT band.

PMID:38610726 SUPPORT REVIEW SYNTHESIS Human Clinical

"In the majority of male androgenetic alopecia cases, a patient's history and clinical evaluation may be sufficient to establish the diagnosis, while for women, they should be supplemented with trichoscopy."

Why the sign matters more in the female pattern.

Peripilar sign on trichoscopy

Show evidence (3 references)

PMID:38610726 SUPPORT REVIEW SYNTHESIS Human Clinical

"The most common features identified using trichoscopy included hair diameter variability (94.07% of patients), vellus hairs (66.45%) and the peripilar sign (43.27%)."

Pooled frequency of 43.27%, in the FREQUENT band.

PMID:38610726 SUPPORT REVIEW SYNTHESIS Human Clinical

"The peripilar sign was more common in men (63.67%) than women (42.53%) (Table 1). The analysis showed that the calculated specificity was the highest among all the features (96.06%)."

The sex difference and the specificity that makes the sign diagnostically useful.

PMID:38610726 SUPPORT REVIEW SYNTHESIS Human Clinical

"A conspicuous brown halo, also known as the peripilar sign, indicates perifollicular inflammation"

What the sign is and what it is taken to reflect, tying it to the microinflammation node.

🧬

Genetic Associations

Polygenic susceptibility with several hundred common loci

relationship_type: SUSCEPTIBILITY

Show evidence (5 references)

PMID:30573740 SUPPORT PRIMARY RESULT Human Clinical

"We detect 624 near-independent genome-wide loci, contributing SNP-heritability of 0.25 (SE = 0.01), of which 26 X-chromosome loci explain 11.6%."

The abstract reports the initial 624 COJO signals; the full body removes two residual-LD X signals, and 11.6% uses selected-SNP variance as denominator.

PMID:22693459 SUPPORT PRIMARY RESULT Human Clinical

"Individuals in the highest risk quartile of a genotype score had an approximately six-fold increased risk of early-onset AGA [odds ratio (OR) = 5.78, p = 1.4×10⁻⁸⁸]."

The top-versus-bottom quartile odds ratio is from an extreme case-control validation sample, not sixfold absolute population risk.

PMID:22693459 SUPPORT PRIMARY RESULT Human Clinical

"Unexpectedly, we identified a risk allele at 17q21.31 that was recently associated with Parkinson's disease (PD) at a genome-wide significant level."

The shared 17q21.31 haplotype behind the reported pleiotropy.

+ 2 more references

Gene: AR hgnc:644 relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE

Show evidence (3 references)

PMID:15902657 SUPPORT PRIMARY RESULT Human Clinical

The candidate functional variant at the locus.

PMID:11231320 SUPPORT REVIEW SYNTHESIS Human Clinical

"The androgen receptor gene StuI restriction site was found in all but one (98.1%) of the 54 young bald men (p = 0.0005) and in 92.3% of older balding men (p = 0.000004) but in only 76.6% of nonbald men."

The original association at the AR locus.

PMID:18385763 SUPPORT PRIMARY RESULT Human Clinical

"We found that the non-synonymous SNP rs1385699 on EDA2R gave the best result (P=3.9e(-19)) whereas rs6152 on the AR gene is less significant (P=4.17e(-12))."

The competing assignment of the X-linked signal to EDA2R, recorded here so that the AR entry does not overstate its case.

EDA2R

Gene: EDA2R hgnc:17756 relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE

Show evidence (2 references)

PMID:18385763 SUPPORT PRIMARY RESULT Human Clinical

"In particular, we found that rs1352015 located 8 kb from the EDA2R gene showed the best result (P=7.77e(-7))."

The lead marker near EDA2R in the genome-wide X-chromosome scan.

PMID:27060448 REFUTE PRIMARY RESULT In Vitro

"We found evidence for AR but not EDA2R as the candidate gene at the AGA risk locus on chromosome X."

Expression in balding papilla cells does not support EDA2R as the functional gene; recorded as REFUTE of the functional-gene claim, not of the association.

20p11.22 locus (PAX1/FOXA2 region)

relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE

Show evidence (2 references)

PMID:18849991 SUPPORT PRIMARY RESULT Human Clinical

"We conducted a genome-wide association study for androgenic alopecia in 1,125 men and identified a newly associated locus at chromosome 20p11.22, confirmed in three independent cohorts (n = 1,650; OR = 1.60, P = 1.1 x 10(-14) for rs1160312)."

Discovery and replication of the locus.

PMID:18849994 SUPPORT PRIMARY RESULT Human Clinical

"We then investigated the 30 best SNPs in an independent replication sample and found highly significant association for five SNPs on chromosome 20p11 (rs2180439 combined P = 2.7 x 10(-15))."

The simultaneous independent discovery.

WNT10A

Gene: WNT10A hgnc:13829 relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE

Show evidence (1 reference)

PMID:23358095 SUPPORT PRIMARY RESULT Human Clinical

"Expression studies in human hair follicle tissue suggest that WNT10A has a functional role in AGA etiology."

The expression evidence that the locus acts through WNT10A.

💊

Medical Actions

Topical minoxidil

Action: Pharmacotherapy NCIT:C15986

Agent: minoxidil CHEBI:6942

Platform: Small molecule

Topical minoxidil is an established treatment for adult male- and female-pattern hair loss. The S3 guideline recommends 2–5% solution or 5% foam twice daily in men, and 2% solution twice daily or 5% foam once daily in women. Assess response after about six months and continue effective therapy to maintain benefit. Temporary early shedding, irritation, contact allergy and unwanted hair growth should be discussed; the guideline advises pausing treatment during pregnancy and lactation. The follicular mechanism remains incompletely defined.

Mechanism Target:

INHIBITS Shortened Anagen — Animal hair-cycle studies support earlier anagen entry and possible anagen prolongation. The exact human mechanism and the fraction of benefit attributable to this effect remain uncertain.

Show evidence (2 references)

PMID:14996087 SUPPORT REVIEW SYNTHESIS Model Organism

"In animal studies, topical minoxidil shortens telogen, causing premature entry of resting hair follicles into anagen, and it probably has a similar action in humans."

The review explicitly distinguishes demonstrated animal cycle changes from proposed human similarity.

PMID:14996087 SUPPORT REVIEW SYNTHESIS Model Organism

"Minoxidil may also cause prolongation of anagen and increases hair follicle size."

Anagen prolongation is a proposed contributor in the mechanism review.

Show evidence (3 references)

PMID:12196747 SUPPORT PRIMARY RESULT Human Clinical

"In men with AGA, 5% topical minoxidil was clearly superior to 2% topical minoxidil and placebo in increasing hair regrowth, and the magnitude of its effect was marked (45% more hair regrowth than 2% topical minoxidil at week 48)."

The randomized male trial supports 5% topical efficacy; its relative gain does not apply to all preparations or populations.

url:https://generolon.com/img/articles/Evidence-based-guideline-for-the-treatment-of-AGA-in-women-and-in-men.pdf SUPPORT REVIEW SYNTHESIS Other

"The response to treatment should be assessed at 6 months. If successful, treatment needs to be continued to maintain efﬁcacy."

Guideline monitoring and continuation advice.

url:https://generolon.com/img/articles/Evidence-based-guideline-for-the-treatment-of-AGA-in-women-and-in-men.pdf SUPPORT REVIEW SYNTHESIS Other

"It is recommended to pause topical minoxidil use during pregnancy and lactation, due to lack of data during this period."

Pregnancy and lactation guidance is precautionary because of limited data.

Low-dose oral minoxidil

Action: Pharmacotherapy NCIT:C15986

Agent: minoxidil CHEBI:6942

Platform: Small molecule

Oral minoxidil is used off-label for hair loss when topical treatment is unsuitable or insufficient. In a 24-week double-dummy trial of 90 selected men, 5 mg daily was not superior to 5% topical minoxidil twice daily for the primary absolute hair-density outcomes; this superiority trial does not establish equivalence. Hypertrichosis and headache were more frequent orally, and men with cardiac or renal disease were excluded. A 43-expert Delphi statement provides prescribing guidance, including cardiovascular and renal precautions and avoidance during pregnancy or breastfeeding; it is not proof of comparative safety. Regimen choice and monitoring require individual assessment.

Mechanism Target:

INHIBITS Shortened Anagen — A possible hair-cycle effect of oral minoxidil is extrapolated from explicitly topical animal studies. This does not directly demonstrate anagen prolongation at the low oral doses used in patients.

Show evidence (2 references)

PMID:14996087 SUPPORT INDIRECT REVIEW SYNTHESIS Model Organism

"In animal studies, topical minoxidil shortens telogen, causing premature entry of resting hair follicles into anagen, and it probably has a similar action in humans."

The review explicitly distinguishes demonstrated animal cycle changes from proposed human similarity.

PMID:14996087 SUPPORT INDIRECT REVIEW SYNTHESIS Model Organism

"Minoxidil may also cause prolongation of anagen and increases hair follicle size."

Anagen prolongation is a proposed contributor in the mechanism review.

Show evidence (3 references)

url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11007651/ SUPPORT PRIMARY RESULT Human Clinical

"In this double-blind, placebo-controlled randomized clinical trial including 90 men with androgenetic alopecia, daily oral minoxidil, 5 mg, was well tolerated and did not demonstrate superiority over topical minoxidil, 5%, in men with androgenetic alopecia after 24 weeks of treatment."

The randomized comparison does not establish equivalence or long-term safety.

url:https://www.newswise.com/pdf_docs/173213268899494_jamadermatology_akiska_2024_cs_240009_1732051708.84641%20%281%29.pdf SUPPORT REVIEW SYNTHESIS Other

"Contraindications for the use of LDOM Ongoing other drug therapy with significant oral minoxidil interaction 38 (86.4) 1 History of pericardial effusion/tamponade 36 (81.8) 1 History of pericarditis 32 (72.7) 1 Congestive heart failure 34 (79.1) 2 History of pulmonary hypertension associated..."

The consensus table defines contraindications; its counts are expert votes rather than adverse-event rates.

url:https://www.newswise.com/pdf_docs/173213268899494_jamadermatology_akiska_2024_cs_240009_1732051708.84641%20%281%29.pdf SUPPORT REVIEW SYNTHESIS Other

"Precautions for the use of LDOM History of tachycardia or other arrhythmia 36 (81.8) 1 Hypotension (blood pressure <90/60 mm Hg) 34 (77.3) 1 Kidney function impairment 38 (88.4) 2 Patients undergoing dialysis 38 (88.4) 2"

The listed cardiovascular and renal precautions inform individualized prescribing.

Finasteride

Action: Pharmacotherapy NCIT:C15986

Agent: finasteride CHEBI:5062

Platform: Small molecule

Oral finasteride 1 mg daily inhibits type 2 5-alpha-reductase and is an established option for adult men with mild-to-moderate male-pattern hair loss. In two trials with 1,553 men during year one, target-area differences versus placebo were 107 hairs at one year and 138 at two years; these are between-group differences, not simple gains from baseline. Response may require 6–12 months and ongoing therapy. Counsel about sexual adverse effects and reduced PSA values. The 2025 EMA review confirms suicidal ideation as an adverse effect of finasteride tablets of unknown frequency and advises men taking 1 mg for hair loss to stop and seek advice if mood changes occur. Pregnancy exposure is contraindicated. The negative 1-mg postmenopausal-women trial does not exclude every female dose or subgroup.

Mechanism Target:

INHIBITS Local Dihydrotestosterone Production — Blocks type 2 5-alpha-reductase, the enzyme of this node, lowering scalp dihydrotestosterone.

Show evidence (1 reference)

PMID:9777765 SUPPORT Human Clinical

"Finasteride, an inhibitor of type II 5alpha-reductase, decreases serum and scalp DHT by inhibiting conversion of testosterone to DHT."

The drug acts on exactly the conversion this node describes.

INHIBITS Follicular Miniaturization — Reduced androgen drive is associated with clinical regrowth and a histologic trend toward less miniaturization; this does not establish restoration of every proposed cellular mechanism.

Show evidence (1 reference)

PMID:12573818 SUPPORT Human Clinical

"Controlled clinical trials with finasteride demonstrated improvements in scalp hair growth in treated men associated with reductions in scalp DHT content, and a trend towards reversal of scalp hair miniaturization was evident by histopathologic evaluation of scalp biopsies."

The review reports a histological trend toward reversal of miniaturization, not uniform restoration of every follicle.

Show evidence (6 references)

PMID:9777765 SUPPORT Human Clinical

"In men with male pattern hair loss, finasteride 1 mg/d slowed the progression of hair loss and increased hair growth in clinical trials over 2 years."

The pivotal trial conclusion.

PMID:9777765 SUPPORT Human Clinical

"Clinically significant increases in hair count (baseline = 876 hairs), measured in a 1-inch diameter circular area (5.1 cm2) of balding vertex scalp, were observed with finasteride treatment (107 and 138 hairs vs placebo at 1 and 2 years, respectively; P < .001)."

The magnitude of the effect on hair counts.

PMID:12573818 SUPPORT Human Clinical

"In contrast to its beneficial effects in men, finasteride did not improve hair growth in postmenopausal women with FPHL."

The 1-mg postmenopausal trial limits generalization of efficacy to that population; it does not refute efficacy in men.

+ 3 more references

Dutasteride

Action: Pharmacotherapy NCIT:C15986

Agent: dutasteride CHEBI:521033

Platform: Small molecule

Dutasteride inhibits type 1 and type 2 5-alpha-reductase. A 416-man, 24-week dose-ranging trial showed increasing hair counts with dose; superiority over finasteride involved dutasteride 2.5 mg versus finasteride 5 mg, not a 0.5-versus-1-mg comparison. The S3 guideline considers 0.5 mg daily as an off-label second-line option after ineffective finasteride treatment. Sexual and reproductive precautions require counseling. The 2025 EMA review did not establish a causal link between dutasteride and suicidal ideation; a warning was added as a class precaution, which should not be described as the same proven drug-specific finding as for finasteride.

Mechanism Target:

INHIBITS Local Dihydrotestosterone Production — Dual 5-alpha-reductase inhibition reduces measured scalp and serum DHT in the dose-ranging trial.

Show evidence (1 reference)

PMID:17110217 SUPPORT Human Clinical

"Scalp and serum dihydrotestosterone levels decreased, and testosterone levels increased, in a dose-dependent fashion with dutasteride."

The pharmacodynamic effect on the node's product.

Show evidence (3 references)

PMID:17110217 SUPPORT Human Clinical

"Dutasteride increased target area hair count versus placebo in a dose-dependent fashion and dutasteride 2.5 mg was superior to finasteride at 12 and 24 weeks."

The randomized comparison against placebo and finasteride.

url:https://generolon.com/img/articles/Evidence-based-guideline-for-the-treatment-of-AGA-in-women-and-in-men.pdf SUPPORT REVIEW SYNTHESIS Other

"In case of ineffective treatment with 1 mg ﬁnasteride over 12 months, the off-label use of dutasteride 0.5 mg/day can be considered."

Guideline second-line consideration, not a universal escalation requirement.

url:https://www.ema.europa.eu/en/documents/referral/finasteride-dutasteride-containing-medicinal-products-article-31-referral-measures-minimise-risk-suicidal-thoughts-finasteride-dutasteride-medicines_en.pdf SUPPORT REVIEW SYNTHESIS Other

"Although it was not possible to establish a link between suicidal ideation and dutasteride based on the reviewed data, dutasteride works in the same way as finasteride and therefore information about the EMA/142716/2025 Page 2/4 mood changes seen with finasteride will also be added to..."

The dutasteride warning is precautionary rather than confirmation of a causal association.

Spironolactone for female-pattern hair loss

Action: Pharmacotherapy NCIT:C15986

Agent: spironolactone CHEBI:9241

Platform: Small molecule

Spironolactone is an off-label option in selected women, with pregnancy avoidance and assessment of renal function, potassium and blood-pressure risks. The older uncontrolled series combining spironolactone and cyproterone groups reported regrowth in 44% and stability in 44%, without proving efficacy against natural history. A 2025 pilot randomized 48 healthy premenopausal women to spironolactone 100 mg or placebo, both with topical 3% minoxidil for 24 weeks. The primary total and terminal hair-count differences were not statistically significant; a dichotomized photographic improvement endpoint favored spironolactone. Menstrual irregularity occurred in 9 of 24 assigned spironolactone and led to two withdrawals. These small adjunct data do not establish benefit in all female-pattern populations.

Mechanism Target:

INHIBITS Dihydrotestosterone-Androgen Receptor Signaling — Androgen-receptor antagonism is the pharmacologic rationale for selected use. Clinical hair-count response does not demonstrate dermal-papilla receptor mediation in every woman.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK430924/ SUPPORT REVIEW SYNTHESIS In Vitro

"androgen receptor, physiologically behaving like a direct antagonist."

The chapter summarizes receptor antagonism; this is separate from clinical response evidence.

Show evidence (2 references)

PMID:15787815 SUPPORT PRIMARY RESULT Human Clinical

"Thirty-five (44%) women had hair regrowth, 35 (44%) had no clear change in hair density before and after treatment, and 10 (12%) experienced continuing hair loss during the treatment period."

Uncontrolled responses cannot distinguish treatment effect from natural history.

PMID:40978669 SUPPORT PRIMARY RESULT Human Clinical

"However, only the P-value of terminal hair counts approached the cutoff of statistical significance (P = .063)."

The primary hair-count comparison was imprecise and not statistically significant.

Low-level laser therapy (photobiomodulation)

Action: low-level laser (photobiomodulation) therapy Ontology label: Photobiomodulation Therapy NCIT:C21063

Platform: Device

Specific low-level laser devices can increase terminal hair density. Four sham-controlled trials randomized 269 adults, with 225 having at least one post-randomization efficacy assessment. At 26 weeks, the pooled adjusted between-group difference was 15.27 hairs/cm²; reported 18–26-hair gains were within active-treatment groups, not the difference versus sham. Participants were predominantly Caucasian, and long-term durability and the optimal device regimen remain uncertain. The S3 guideline suggests LLLT as ancillary care using devices with trial-supported energy settings.

Mechanism Target:

INHIBITS Patterned non-scarring scalp hair loss — Reported hair-density improvement addresses visible scalp thinning. The cited endpoint does not establish reversal of miniaturized follicle histology or a specific cellular mechanism.

Show evidence (1 reference)

PMID:24474647 SUPPORT PRIMARY RESULT Human Clinical

"The overall results showed the least squares mean difference of change in terminal hair density of 15.27 (standard error 1.781) at 26 weeks from baseline between lasercomb- and sham treated subjects, which was highly statistically significant (p < 0.0001)."

The pooled adjusted difference is the between-group treatment estimate.

Show evidence (2 references)

PMID:24474647 SUPPORT Human Clinical

"Randomized, sham device-controlled, double-blind clinical trials were conducted at multiple institutional and private practices."

The design of the trials supporting the device.

PMID:24474647 SUPPORT PRIMARY RESULT Human Clinical

The pooled adjusted difference is the between-group treatment estimate.

Platelet-rich plasma injection

Action: autologous platelet-rich plasma scalp injection Ontology label: Therapeutic Procedure NCIT:C49236

Platform: Other

Autologous platelet-rich plasma scalp injection has shown improved hair-density outcomes in pooled trials, but preparation, activation, injection schedule and outcomes differ. The cited meta-analysis reports a standardized mean difference of 0.51 versus placebo; this is not an absolute hair count. The 2018 S3 guideline could not recommend for or against PRP because of limited evidence and absent standardization, while a 2025 Canadian Delphi panel recommends it. These are different evidence dates and consensus processes. Patient growth-factor mediation and an optimal maintenance schedule remain unresolved.

Mechanism Target:

Show evidence (1 reference)

PMID:30882509 SUPPORT Human Clinical

"The overall SMD in hair density was 0.58 (95% confidence interval [CI]: 0.35-0.80) and 0.51 (95% CI: 0.23-0.80, p < .0004) in favor of PRP treatment when compared with baseline and placebo treatment, respectively."

The pooled effect size against baseline and placebo.

Show evidence (2 references)

PMID:30882509 SUPPORT Human Clinical

The pooled effect size against baseline and placebo.

PMID:40986632 SUPPORT REVIEW SYNTHESIS Other

"Seven interventions are recommended, including oral dutasteride; oral finasteride; topical finasteride; topical minoxidil; platelet-rich plasma; microneedling; and oral minoxidil."

The 2025 Canadian panel recommendation is consensus, not a new trial.

Hair transplantation (follicular unit transplantation or extraction)

Action: hair transplantation Ontology label: Hair-Bearing Skin Graft Transplantation NCIT:C219973

Platform: Surgery

Follicular-unit transplantation or extraction redistributes donor hair to affected scalp and can improve coverage in appropriately selected patients. Adequate donor supply, realistic expectations and stable or medically controlled disease are important. Extraction avoids a linear donor incision but is not scar-free, and transplanted coverage does not prevent progression of native susceptible hair. The S3 guideline considers surgery in suitable men and women; combination medical therapy may help preserve non-transplanted hair.

Mechanism Target:

BYPASSES Follicular Miniaturization — Transplantation adds donor follicles to thinning areas rather than reversing miniaturization in the pre-existing affected follicles.

Show evidence (1 reference)

PMID:12174065 SUPPORT PRIMARY RESULT Human Clinical

"FUE is a minimally invasive approach to hair transplantation that obviates the need for a linear donor incision."

The intervention moves follicular units and changes coverage, not the molecular state of resident follicles.

Show evidence (3 references)

PMID:16039422 SUPPORT Other

"The recognition that the follicular unit is a discrete, anatomic and physiologic entity, and that preserving it through stereomicroscopic dissection is the best way to ensure the naturalness of the restoration, has brought hair transplantation into the twenty-first century."

The follicular unit principle behind modern transplantation.

PMID:16039422 SUPPORT Other

"The essence of providing the best care for patients rests on proper patient selection, establishing realistic expectations, and using nonsurgical management for young persons who are just starting to thin."

Patient selection and the place of medical therapy first.

PMID:12174065 SUPPORT Human Clinical

"FUE is a minimally invasive approach to hair transplantation that obviates the need for a linear donor incision."

The extraction alternative to strip harvest.

Microneedling adjunct to topical minoxidil

Action: scalp microneedling (dermaroller) with topical minoxidil Ontology label: Therapeutic Procedure NCIT:C49236

Platform: Device

Scalp microneedling is used as an adjunct to topical therapy. A 12-week pilot randomized 100 men to weekly 1.5-mm microneedling plus 5% minoxidil or minoxidil alone; 94 were analyzed, with all six early dropouts in the minoxidil-only arm. Hair-count gains were 91.4 versus 22.2 per cm², but patient-reported improvement was unblinded and long-term durability was not established. The study did not measure patient Wnt activation or stem-cell conversion. Later consensus recommendations exist, so it is not accurately described as a single unreplicated intervention.

Mechanism Target:

Show evidence (1 reference)

PMID:23960389 SUPPORT PRIMARY RESULT Human Clinical

"The mean change in hair count at week 12 was significantly greater for the Microneedling group compared to the Minoxidil group (91.4 vs 22.2 respectively)."

The pilot measures short-term hair-count change, not Wnt activation or histological reversal.

Show evidence (4 references)

PMID:23960389 SUPPORT Human Clinical

"After randomization one group was offered weekly microneedling treatment with twice daily 5% minoxidil lotion (Microneedling group); other group was given only 5% minoxidil lotion."

The combination-versus-minoxidil-alone design.

PMID:23960389 SUPPORT Human Clinical

"The mean change in hair count at week 12 was significantly greater for the Microneedling group compared to the Minoxidil group (91.4 vs 22.2 respectively)."

The primary hair-count result favouring the combination.

PMID:23960389 SUPPORT Human Clinical

"In the Microneedling group, 41 (82%) patients reported more than 50% improvement versus only 2 (4.5%) patients in the Minoxidil group. Unsatisfied patients to conventional therapy for AGA got good response with Microneedling treatment."

Patient-assessed response and the response in prior non-responders.

+ 1 more reference

Topical finasteride

Action: Pharmacotherapy NCIT:C15986

Agent: finasteride CHEBI:5062

Platform: Small molecule

A formulation-specific 24-week trial randomized 458 men aged 18–40 with mild-to-moderate vertex hair loss to topical finasteride 0.25% spray, placebo or oral finasteride 1 mg. Topical treatment improved target-area hair count versus placebo; the protocol-defined primary analysis included only 250 men with valid baseline and on-treatment photographs, although post hoc sensitivity analyses supported the direction of benefit. Numerical similarity to oral treatment does not establish efficacy equivalence. Plasma exposure was substantially lower with topical treatment, but serum DHT still fell and systemic adverse effects remain possible. Low sexual-event counts and short follow-up do not establish superior long-term safety. Evidence for this specific spray should not be generalized to every compounded formulation or to women.

Mechanism Target:

INHIBITS Patterned non-scarring scalp hair loss — The trial measures improvement in vertex hair count; it does not demonstrate reversal of each proposed cellular mechanism or increased hair width.

Show evidence (1 reference)

PMID:34634163 SUPPORT PRIMARY RESULT Human Clinical

"At week 24, the adjusted mean change from baseline in TAHC was significantly greater with topical finasteride than with placebo (20.2 vs. 6.7 hairs; P < 0.001), and was numerically similar to that with oral finasteride (21.1 hairs; Fig. 3)."

The primary hair-count comparison supports superiority to placebo; the numerical oral comparison was not an efficacy-equivalence test.

Show evidence (4 references)

PMID:34634163 SUPPORT PRIMARY RESULT Human Clinical

The primary hair-count comparison supports superiority to placebo; the numerical oral comparison was not an efficacy-equivalence test.

PMID:34634163 SUPPORT PRIMARY RESULT Human Clinical

"Overall, 250 patients (54.6%) had evaluable hair count measurements from the macrophotographs both at baseline and on treatment and formed the ITT population."

Only 250 of 458 randomized participants entered the protocol-defined primary efficacy analysis because valid baseline and on-treatment macrophotographs were required.

PMID:34634163 SUPPORT PRIMARY RESULT Human Clinical

"Mean serum DHT concentrations at week 24 were 34.6% lower than at baseline in the topical finasteride group (25.75 vs. 39.32 ng/dL, respectively), and were 55.6% lower than at baseline in the oral finasteride group (15.75 vs. 35.50 ng/dL, respectively)."

Serum DHT remained suppressed with topical treatment, despite lower systemic finasteride exposure. The full results report 34.6%, rounded differently from the abstract.

+ 1 more reference

🌍

Environmental Factors

Tobacco smoking

Smoking is associated with AGA presence and with greater cross-sectional severity in observational studies. In the 2026 review, the endpoint labeled progression compared moderate/severe with mild disease; no cohort studies established longitudinal worsening. Proposed oxidative or inflammatory mechanisms remain untested in the cited scalp evidence, and the association does not demonstrate that smoking cessation reverses AGA.

Show evidence (2 references)

PMID:41606541 SUPPORT Human Clinical

"Family history (presence: odds ratio [OR] 2.72, 95% confidence interval [CI] 1.85–3.99; progression: OR 4.24, 95% CI 2.77–6.49) and smoking (presence: OR 1.46, 95% CI 1.06–2.01; progression: OR 1.60, 95% CI 1.29–1.99) were significantly associated with both presence and progression of AGA."

The reported progression odds ratio refers to cross-sectional severity categories; it is not a longitudinal progression rate.

PMID:12673073 SUPPORT Other

"Smoke-induced premature skin ageing has attracted the attention of the medical community, while only recently an observational study has indicated a significant relationship between smoking and baldness."

The observational nature of the association as the review itself states it.

Mechanism Target:

EXACERBATES Perifollicular Inflammation — Pro-oxidant effects of smoke are proposed to release pro-inflammatory cytokines and drive follicular microinflammation and fibrosis; the mechanism is proposed from general smoke biology rather than shown in scalp.

Show evidence (1 reference)

PMID:12673073 SUPPORT INDIRECT REVIEW SYNTHESIS Other

"pro-oxidant effects of smoking leading to the release of pro-inflammatory cytokines resulting in follicular micro-inflammation and fibrosis"

The proposed route from smoke to the perifollicular inflammatory node; a review's mechanistic proposal, hence indirect.

🔬

Diagnosis

Clinical pattern recognition with trichoscopy

Diagnosis is usually clinical, based on gradual patterned nonscarring thinning and examination of the scalp. A negative family history does not exclude it. Trichoscopy can support the diagnosis and distinguish other alopecias, but heterogeneous research estimates do not establish a universal diagnostic cutoff. Follicular ostial loss, marked inflammation, rapid shedding or atypical distribution prompt assessment for an alternative or coexisting condition.

Show evidence (2 references)

PMID:38610726 SUPPORT REVIEW SYNTHESIS Human Clinical

"We concluded that hair diameter variability, vellus hairs and the peripilar sign represented valuable indicators for the diagnosis of androgenetic alopecia."

The trichoscopic criteria from a systematic review of 34 studies.

PMID:10882953 SUPPORT REVIEW SYNTHESIS Human Clinical

"Only exceptionally laboratory tests or scalp biopsies are needed to confirm the diagnosis."

The place of tests and biopsy in diagnosis.

Selective laboratory and endocrine evaluation

Testing is guided by history and examination rather than a routine hormonal panel for every patient. Ferritin or thyroid evaluation may be appropriate with diffuse shedding or relevant symptoms. Women with hirsutism, acne, menstrual disturbance or other androgen-excess features may need endocrine assessment; unusually early onset warrants pediatric or endocrine evaluation.

Show evidence (1 reference)

url:https://bhns.org.uk/ccs_files/web_data/Resources/Guidelines/european%20S1%20AGA%20guidelien.pdf SUPPORT REVIEW SYNTHESIS Other

"Measurement of ferritin level or thyroid-stimulating hormone may be considered depending on the individual history, espe- cially in diffuse efﬂuvium."

The S1 document provides expert diagnostic guidance rather than a validated screening algorithm.

Scalp biopsy when the diagnosis is uncertain

Biopsy is reserved for diagnostic uncertainty, particularly diffuse alopecia areata or suspected scarring alopecia. Horizontal sections quantify follicular populations; vertical sections provide complementary inflammatory and scarring information. Cohort-specific terminal-to-vellus ratios are interpreted with the clinical pattern rather than used as a universal stand-alone test.

Show evidence (2 references)

PMID:10882953 SUPPORT REVIEW SYNTHESIS Human Clinical

"Only exceptionally laboratory tests or scalp biopsies are needed to confirm the diagnosis."

The clinical review reserves laboratory investigations and biopsy for selected diagnostic circumstances.

PMID:8496421 SUPPORT PRIMARY RESULT Human Clinical

Horizontal follicle counts were useful in this selected biopsy series, without establishing population-level sensitivity.

📊

Prevalence

Men aged 18-49, US community sample

Point Prevalence 42000.0 per 100,000 >1 in 1,000

The US community sample reported Norwood type III or greater in 42% of examined men aged 18–49. Separate age-stratum rates were 16% at 18–29 and 53% at 40–49; these are not confidence-interval bounds.

Show evidence (2 references)

PMID:9865198 SUPPORT PRIMARY RESULT Human Clinical

"The proportion of men with moderate to extensive hair loss increased with increasing age, ranging from 16% for men 18-29 years of age to 53% of men 40-49."

The age-stratified prevalence in a community sample.

PMID:9865198 SUPPORT PRIMARY RESULT Human Clinical

"The proportion of men with moderate to extensive hair loss (type III or greater) was 42%."

The overall figure recorded as the rate.

Men aged 46, Northern Finland Birth Cohort 1966

Point Prevalence 68500.0 per 100,000 >1 in 1,000

AGA was identified in 611 of 892 examined men (68.5%) aged 45.3–47.6 in the Oulu-area follow-up. Of 3,181 invited cohort members of both sexes, 1,932 attended; this is not an examination of the entire birth cohort. Mild/moderate/severe percentages 39.0/33.2/27.8 use the 611 affected men as denominator.

Show evidence (1 reference)

PMID:39192534 SUPPORT PRIMARY RESULT Human Clinical

"AGA was found in 68.5% of subjects, 27.8% of the cases were severe, 33.2% moderate and 39.0% mild."

Dermatologist-ascertained prevalence among the examined Oulu-area male follow-up participants; subtype percentages use cases as denominator.

Older Caucasian men, review estimate

Point Prevalence 80000.0 per 100,000 >1 in 1,000

The S3 guideline summarizes signs of AGA in up to 80% of Caucasian men by age 70 or later. This is an age-specific review estimate, not a prospectively measured lifetime incidence or a rate applicable across ancestries.

Show evidence (1 reference)

url:https://generolon.com/img/articles/Evidence-based-guideline-for-the-treatment-of-AGA-in-women-and-in-men.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"By the age of 70 or beyond, 80% of Caucasian men and up to 40% of women have signs of AGA."

The guideline summarizes an age-specific estimate from prior epidemiology.

Women, Caucasian

Point Prevalence Common

A survey of 1,006 Caucasian women describes female-pattern hair loss as common with increasing occurrence in adult life. The S3 guideline summarizes up to 40% by age70 or later; age, ascertainment and case definition vary, so no uniform cohort rate is assigned.

Show evidence (2 references)

PMID:11231244 SUPPORT PRIMARY RESULT Human Clinical

"Female androgenetic alopecia is quite common beginning in the late 20s and reaching its peak after 50 years of age."

The qualitative frequency and age course in women.

url:https://generolon.com/img/articles/Evidence-based-guideline-for-the-treatment-of-AGA-in-women-and-in-men.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"By the age of 70 or beyond, 80% of Caucasian men and up to 40% of women have signs of AGA."

This review estimate is age- and population-specific rather than a universal female lifetime rate.

🔀

Differential Diagnoses

Conditions with similar clinical presentations that must be differentiated from Androgenetic Alopecia:

Telogen effluvium

Overlapping Features Diffuse shedding without patterned miniaturization, often with a precipitant three months earlier. Distinguished by a positive pull test across the whole scalp, absence of hair-diameter variability, and a normal terminal-to-vellus ratio on biopsy. The two commonly coexist in women.

Alopecia areata

Overlapping Features Autoimmune, non-scarring, and typically patchy, with exclamation-mark hairs, black dots and yellow dots on trichoscopy and a peribulbar lymphocytic infiltrate rather than miniaturization. A diffuse variant can mimic the female pattern.

Frontal fibrosing alopecia and lichen planopilaris

Overlapping Features Scarring alopecias in which follicular ostia are lost. Frontal fibrosing alopecia recedes the frontal hairline band-like with loss of eyebrows, and a pattern-distributed fibrosing variant of lichen planopilaris is the main scarring mimic of the female pattern; both need biopsy when suspected.

Traction alopecia and trichotillomania

Overlapping Features Mechanical causes with a distribution that follows hairstyle or hand, and with broken hairs of varying length in trichotillomania.

Hyperandrogenic disorders in women

Overlapping Features Polycystic ovary syndrome, androgen-secreting tumours and adrenal disorders can produce a male-type pattern with hirsutism, acne and menstrual disturbance; these signs, not the hair loss itself, prompt endocrine testing.

🔬

Clinical Trials

NCT05888922 PHASE_III ACTIVE_NOT_RECRUITING

International, multicentre, randomized, double-blind phase III trial of oral minoxidil 1 mg once daily in women with androgenetic alopecia, double-dummy controlled against both placebo and topical 2 percent minoxidil solution, with hair density by photography as the efficacy readout and blood pressure, ECG and hypertrichosis as the safety readouts over up to 36 weeks. Planned enrolment about 520. The registered test of the oral route that is currently used off-label; registry status active, not recruiting, as of September 2026.

Target Phenotypes: Diffuse central scalp thinning (Ludwig pattern) HP:0002209

Show evidence (2 references)

clinicaltrials:NCT05888922 SUPPORT BACKGROUND Other

"The main questions to answer are to know about that minoxidil 1mg is as effective as minoxidil 2% topical solution (comparator product) and is more effective than placebo; and to ensure treatment with oral minoxidil is safe."

The registered objectives: non-inferiority to topical minoxidil, superiority to placebo, and safety of the oral route in women.

clinicaltrials:NCT05888922 SUPPORT BACKGROUND Other

"At the visits, the following examinations will be performed: photos of the hair will be taken to determine hair density, assessment of changes in scalp hair growth, measurement of blood pressure, pulse, and body temperature, a physical examination, blood withdrawal to determine any abnormalities..."

The efficacy and safety readouts, which cover exactly the concerns (blood pressure, ECG, hypertrichosis) that the off-label use raises.

NCT07529977 PHASE_III NOT_RECRUITING

Phase 3, randomized, double-blind, placebo-controlled multicentre trial in Brazil of N1087, an oral minoxidil formulation titrated over 8 weeks to a maximum tolerated dose not exceeding 5 mg and then continued for 16 weeks, in men aged 18 to 60 with Norwood-Hamilton 3V, 4 or 5 disease, randomized 2 to 1 against placebo. The primary outcome is the change in non-vellus hair density in a vertex target area at 24 weeks by digital phototrichogram. Planned enrolment about 372; registry status not yet recruiting as of September 2026.

Target Phenotypes: Frontotemporal hairline recession HP:0002292 Vellus-like miniaturized scalp hair HP:0002213

Show evidence (2 references)

clinicaltrials:NCT07529977 SUPPORT BACKGROUND Other

"The main purpose of the study is to assess whether oral minoxidil improves hair growth. The primary outcome measure is the change from baseline in the density of non-vellus hairs in a defined target area of the scalp (vertex) after 24 weeks of treatment, measured using digital phototrichogram analysis."

Identifies N1087 as oral minoxidil and states the primary endpoint, non-vellus hair density, which is the clinical inverse of miniaturization.

clinicaltrials:NCT07529977 SUPPORT BACKGROUND Other

"During the first 8 weeks, the dose will be gradually increased (titration period) up to a maximum tolerated dose, not exceeding 5 mg. Participants will then continue treatment at the maximum tolerated dose for the remaining 16 weeks."

The titrated dosing scheme and the 5 mg ceiling.

NCT06527365 PHASE_II ACTIVE_NOT_RECRUITING

Open-label, multicentre phase 2 study of VDPHL01, an investigational oral tablet, given once daily as 8.5 mg to men and once or twice daily as 4.5 mg to women with androgenetic alopecia for 12 months, with 11 visits over about 13 months. Planned enrolment about 70. The uncontrolled safety and dose-exposure arm of the VDPHL01 programme; registry status active, not recruiting, as of September 2026.

Target Phenotypes: Androgenetic (patterned) alopecia HP:0001596

Show evidence (2 references)

clinicaltrials:NCT06527365 SUPPORT BACKGROUND Other

"VDPHL01 8.5 mg Tablets for males and VDPHL01 4.5 mg Tablets for females are an investigational oral drug to treat male and female pattern baldness."

The agent, its sex-specific doses and its oral route as registered.

clinicaltrials:NCT06527365 SUPPORT BACKGROUND Other

"Male subjects that meet the study eligibility criteria will be administered VDPHL01 once daily for 12 months. Female subjects that meet the study eligibility criteria will be administered VDPHL01 either once or twice daily for 12 months."

The open-label dosing schedule and duration.

NCT06724614 PHASE_III ACTIVE_NOT_RECRUITING

Randomized, double-blind, placebo-controlled, multicentre study of VDPHL01 8.5 mg tablets once daily in men with androgenetic alopecia: a placebo-controlled period covering the first seven visits followed by an open treatment extension in which all subjects receive active drug, about 13 months in all. Planned enrolment about 480. ClinicalTrials.gov registers the study under the combined designation Phase 2/Phase 3; the schema holds one value, so it is recorded as PHASE_III, the pivotal designation shared by its identically titled sibling NCT06972264. Registry status active, not recruiting, as of September 2026.

Target Phenotypes: Frontotemporal hairline recession HP:0002292

Show evidence (2 references)

clinicaltrials:NCT06724614 SUPPORT BACKGROUND Other

"The first 7 visits will be part of the placebo-controlled period. The next 3 visits will be part of the treatment extension phase. All subjects will receive active drug in the treatment extension phase."

The placebo-controlled period followed by the open extension.

clinicaltrials:NCT06724614 SUPPORT BACKGROUND Other

"VDPHL01 8.5 mg Tablet is an investigational oral drug to treat male pattern baldness."

The agent and dose under test in men.

NCT06972264 PHASE_III ACTIVE_NOT_RECRUITING

Second randomized, double-blind, placebo-controlled, multicentre phase 3 study of VDPHL01 8.5 mg tablets in men with androgenetic alopecia, about 13 months with 11 visits, registered under the same title as NCT06724614. Planned enrolment about 480. Registry status active, not recruiting, as of September 2026.

Target Phenotypes: Frontotemporal hairline recession HP:0002292

Show evidence (1 reference)

clinicaltrials:NCT06972264 SUPPORT BACKGROUND Other

"This multi-center, double blind, study will last about 13 months and includes 11 study visits (screening, baseline (day 1), week 2, month 1, month 2, month 4, month 6, month 8, month 10, month 12, month 13)."

Design, duration and visit schedule as registered.

NCT07146022 PHASE_III ACTIVE_NOT_RECRUITING

Randomized, double-blind, placebo-controlled, multicentre phase 3 study of VDPHL01 in women with androgenetic alopecia, about 13 months with 11 visits, the female counterpart of the two male VDPHL01 phase 3 studies. Planned enrolment about 552. Registry status active, not recruiting, as of September 2026.

Target Phenotypes: Diffuse central scalp thinning (Ludwig pattern) HP:0002209

Show evidence (2 references)

clinicaltrials:NCT07146022 SUPPORT BACKGROUND Other

"This study will evaluate the safety and efficacy of VDPHL01 in female subjects with Androgenetic Alopecia (AGA)."

The registered objective in the female population.

clinicaltrials:NCT07146022 SUPPORT BACKGROUND Other

"VDPHL01 is an investigational oral drug to treat AGA."

The agent and route.

NCT07563036 NOT_APPLICABLE RECRUITING

Prospective single-arm, pre-post mechanistic study (Kasr El Aini Hospital, about 25 patients) measuring tissue Janus kinase 2 expression in balding against non-balding scalp at baseline and again in balding scalp after 3 months of topical minoxidil 5 percent, with trichoscopic parameters as the clinical readout. Not a phase-classified drug trial; it tests whether a JAK2 signal exists in balding scalp and whether minoxidil moves it, and the record carries no outcome results. Registry status recruiting as of September 2026.

Target Phenotypes: Androgenetic (patterned) alopecia HP:0001596

Show evidence (2 references)

clinicaltrials:NCT07563036 SUPPORT BACKGROUND Other

"This prospective single-arm pre-post interventional study aims to assess tissue Janus Kinase 2 (JAK2) expression in patients with androgenetic alopecia by comparing balding and non-balding scalp at baseline, and to evaluate changes in JAK2 expression in balding scalp after 3 months of topical..."

Design, comparison and intervention as registered.

clinicaltrials:NCT07563036 SUPPORT BACKGROUND Other

"Clinical response will be assessed using standardized trichoscopic parameters."

The clinical readout is trichoscopic, matching the diagnostic features recorded in this entry.

🧫

Experimental Models

Macaque dermal-papilla and outer-root-sheath coculture CO_CULTURE

Testosterone inhibited outer-root-sheath cell proliferation only with adult bald-frontal dermal papilla cells in the cited coculture. The androgen-receptor blocker RU 58841 antagonized inhibition. This model tests site- and age-dependent paracrine response; it does not prove absence of receptors in every unaffected human follicle.

Cell source

Dermal papilla and outer-root-sheath cells from adult frontal/occipital and juvenile frontal macaque scalp

Pathograph links

Dihydrotestosterone-Androgen Receptor Signaling perturbs fidelity: moderate observes: molecular Testosterone and an AR blocker probe androgen-dependent epithelial inhibition mediated by dermal papilla cells.

Limitations: The applied androgen is testosterone; DHT flux and the entire human clinical mechanism are not directly measured.

Show evidence (1 reference)

PMID:8977424 SUPPORT PRIMARY RESULT In Vitro

"Testosterone-induced inhibition of outer root sheath cell proliferation occurred only in coculture with dermal papilla cells derived from the bald scalps of adult macaques but not with dermal papilla cells from the hairy occipital scalps of adult macaques or the prebald frontal scalps of..."

Regional and age-specific response was tested in macaque cell coculture, not inferred from intact-animal hair weight.

Show evidence (2 references)

PMID:8977424 SUPPORT PRIMARY RESULT In Vitro

Regional and age-specific response was tested in macaque cell coculture, not inferred from intact-animal hair weight.

PMID:8977424 SUPPORT PRIMARY RESULT In Vitro

"Furthermore, RU 58841, an androgen receptor blocker, antagonized this testosterone-elicited inhibition."

Antagonism supports receptor involvement within the cell preparation.

AR-transfected human dermal-papilla and keratinocyte coculture CO_CULTURE

Native cultured dermal papilla cells initially showed no significant androgen-dependent inhibition. AR transfection restored the response, with increased TGF-beta1 secretion and antibody-sensitive keratinocyte growth suppression. The engineered receptor context limits extrapolation to untreated patient follicles.

Cell source

Cultured balding-derived human dermal papilla cells with keratinocytes

Pathograph links

Increased TGF-Beta1 Secretion perturbs fidelity: moderate observes: molecular Androgen exposure tests secreted TGF-beta1 in the modified coculture.

Limitations: AR overexpression restores culture responsiveness and may alter quantitative signaling.

Show evidence (1 reference)

PMID:12397096 SUPPORT PRIMARY RESULT In Vitro

"ELISA assays demonstrated that androgen treatment increased the secretion of both total and active TGF-beta1 in the conditioned medium."

Androgen increased secreted TGF-beta1 in AR-transfected dermal papilla culture.

Reduced Follicular Keratinocyte Proliferation measures fidelity: moderate observes: cellular Neutralizing TGF-beta1 reverses the coculture growth inhibition.

Limitations: Keratinocyte population growth is not direct measurement of chronic patient miniaturization.

Show evidence (1 reference)

PMID:12397096 SUPPORT PRIMARY RESULT In Vitro

"Moreover, the neutralizing anti-TGF-beta1 antibody reversed the androgen-elicited growth inhibition of KCs in a dose-dependent manner."

Neutralization supports a TGF-beta1-dependent component.

Show evidence (2 references)

PMID:12397096 SUPPORT PRIMARY RESULT In Vitro

The growth effect occurs in the receptor-transfected preparation.

PMID:12397096 SUPPORT PRIMARY RESULT In Vitro

"ELISA assays demonstrated that androgen treatment increased the secretion of both total and active TGF-beta1 in the conditioned medium."

Androgen increased secreted TGF-beta1 in AR-transfected dermal papilla culture.

Human dermal-papilla Wnt and differentiation coculture CO_CULTURE

Androgen exposure altered beta-catenin/GSK3beta readouts in dermal papilla cells and reduced their ability to induce hair keratin expression in cocultured follicular cells. Wnt activation rescued that differentiation readout. The signaling measurement is in dermal papilla, and the experiment does not directly measure the marker-defined progenitor deficits in paired patient scalp.

Cell source

Human dermal papilla cells and follicular stem-cell preparations

Pathograph links

Reduced Canonical Wnt Signaling in Dermal Papilla Cells perturbs fidelity: moderate observes: molecular Androgen treatment alters the measured pathway state.

Limitations: Assay-specific signaling and differentiation readouts; no patient lineage tracing.

Show evidence (1 reference)

PMID:22283397 SUPPORT PRIMARY RESULT In Vitro

The beta-catenin and GSK3beta measurements were in dermal papilla cells, not the follicular epithelium.

Impaired Follicular Epithelial Differentiation measures fidelity: moderate observes: cellular Hair keratin induction is used as a differentiation readout.

Limitations: Rescue in culture does not establish the complete human disease route.

Show evidence (1 reference)

PMID:22283397 SUPPORT PRIMARY RESULT In Vitro

"Wnt signalling activation restored the ability of androgen-treated DPC to induce differentiation."

Wnt activation rescues the differentiation-inducing activity of androgen-treated dermal papilla cells in coculture.

Show evidence (2 references)

PMID:22283397 SUPPORT PRIMARY RESULT In Vitro

The beta-catenin and GSK3beta measurements were in dermal papilla cells, not the follicular epithelium.

PMID:22283397 SUPPORT PRIMARY RESULT In Vitro

"Wnt signalling activation restored the ability of androgen-treated DPC to induce differentiation."

Wnt activation rescues the differentiation-inducing activity of androgen-treated dermal papilla cells in coculture.

Human terminal follicle organ culture exposed to PGD2 OTHER

PGD2 and 15-dPGJ2 inhibited elongation in terminal follicle cultures from at least three donors per compound. The samples were not established miniaturized AGA scalp follicles. Human GPR44 involvement was inferred from agonist-potency correlation; receptor necessity was tested separately in mice. No clinical regrowth or human stem-cell rescue was demonstrated.

Cell source

Terminal anagen follicles from face/brow-lift tissue of adult women and men

Pathograph links

PGD2-Associated Hair Growth Inhibition perturbs fidelity: moderate observes: cellular Exogenous prostaglandin exposure reduces cultured hair elongation.

Limitations: Donor site, exposure concentration and short culture interval limit disease-level inference.

Show evidence (1 reference)

PMID:22440736 SUPPORT PRIMARY RESULT In Vitro

"We show that PGD(2) inhibits hair growth in explanted human hair follicles and when applied topically to mice."

The paper includes growth inhibition of explanted human follicles; mouse topical experiments are assessed separately.

Show evidence (2 references)

PMID:22440736 SUPPORT PRIMARY RESULT In Vitro

"We show that PGD(2) inhibits hair growth in explanted human hair follicles and when applied topically to mice."

The paper includes growth inhibition of explanted human follicles; mouse topical experiments are assessed separately.

PMID:22440736 SUPPORT PRIMARY RESULT In Vitro

"For hair-lengthening experiments, discarded tissue from face lifts, which contain terminal hair, was used."

The follicle source is terminal hair from discarded face-lift tissue.

🐁

Animal Models

Stump-tailed macaque spontaneous frontal balding

Adult stump-tailed macaques of both sexes can develop frontal follicular regression. In a six-month study, 11 animals received oral finasteride 1 mg/kg/day and 10 received vehicle. Treated animals had greater frontal hair-weight gain than controls and increased follicle length relative to their own baseline. These observations support androgen-sensitive follicular growth in a primate model, not equivalence to the human genetic architecture, pattern or clinical dosing.

Species

Macaca arctoides

Genotype

Wild type; naturally occurring frontal balding

Publication

PMID:7962310

Pathograph links

Follicular Miniaturization partially recapitulates fidelity: moderate observes: tissue The model displays age-related follicular regression and growth responses under DHT-lowering treatment.

Limitations: Small mixed-sex primate study; hair weight and follicle length do not measure human dermal-papilla cell rescue or every miniaturization pathway.

Readouts

Frontal hair weight during finasteride treatment

Direction: INCREASED

Interpretation: Treatment increased hair output compared with vehicle.

Show evidence (1 reference)

PMID:7962310 SUPPORT PRIMARY RESULT Model Organism

"Both males and females showed statistically significant increases in mean hair weight over the treatment period compared to controls (P = 0.034)."

Hair weight increased relative to vehicle in the 21-animal study, distinct from the within-treated baseline follicle-length comparison.

Follicle length during finasteride treatment

Direction: INCREASED

Interpretation: Length increased from baseline within treated animals.

Show evidence (1 reference)

PMID:7962310 SUPPORT PRIMARY RESULT Model Organism

"In addition, there was a statistically significant increase in mean follicle length (measured histologically in scalp biopsies) compared to baseline in the finasteride-treated animals (P = 0.028)."

The follicle-length significance is relative to treated-animal baseline, not stated as a between-group effect in the abstract.

Show evidence (2 references)

PMID:7962310 SUPPORT PRIMARY RESULT Model Organism

"Both males and females showed statistically significant increases in mean hair weight over the treatment period compared to controls (P = 0.034)."

Hair weight increased relative to vehicle in the 21-animal study, distinct from the within-treated baseline follicle-length comparison.

+ 1 more reference

Show evidence (2 references)

PMID:7962310 SUPPORT PRIMARY RESULT Model Organism

"Both males and females showed statistically significant increases in mean hair weight over the treatment period compared to controls (P = 0.034)."

Hair weight increased relative to vehicle in the 21-animal study, distinct from the within-treated baseline follicle-length comparison.

PMID:7962310 SUPPORT PRIMARY RESULT Model Organism

"In addition, there was a statistically significant increase in mean follicle length (measured histologically in scalp biopsies) compared to baseline in the finasteride-treated animals (P = 0.028)."

The follicle-length significance is relative to treated-animal baseline, not stated as a between-group effect in the abstract.

K14-Ptgs2 mouse with altered skin prostanoids

Skin-targeted Ptgs2 overexpression increased PGD2 and 15-dPGJ2, but also PGE2, and was associated with alopecia, miniaturization and sebaceous enlargement. This is an altered-prostanoid model, not proof that PGD2 alone causes all findings. Gpr44 epistasis was not tested in this transgenic background.

Species

Mouse

Genotype

K14-Ptgs2 transgenic

Publication

PMID:22440736

Pathograph links

Prostaglandin D2 Elevation in Bald Scalp perturbs fidelity: moderate observes: molecular Upstream cyclooxygenase overexpression increases skin PGD2.

Limitations: Multiple prostanoids change; the manipulation does not identify the cause of human scalp PGD2 elevation.

Show evidence (1 reference)

PMID:22440736 SUPPORT PRIMARY RESULT Model Organism

The K14-Ptgs2 model changes upstream prostanoid production and develops hair phenotypes; it is not a selective PGD2 manipulation.

Follicular Miniaturization partially recapitulates fidelity: moderate observes: tissue Miniaturization and alopecia accompany altered skin prostanoid production.

Limitations: No selective PGD2 sufficiency or human androgen-pattern mechanism is established.

Show evidence (1 reference)

PMID:22440736 SUPPORT PRIMARY RESULT Model Organism

The K14-Ptgs2 model changes upstream prostanoid production and develops hair phenotypes; it is not a selective PGD2 manipulation.

Show evidence (2 references)

PMID:22440736 SUPPORT PRIMARY RESULT Model Organism

The K14-Ptgs2 model changes upstream prostanoid production and develops hair phenotypes; it is not a selective PGD2 manipulation.

PMID:22440736 SUPPORT PRIMARY RESULT Model Organism

"PGE2 was elevated in the K14-Ptgs2 mice compared to age-matched wild-type controls"

PGE2 elevation demonstrates that the transgenic perturbation is not selective for PGD2.

Topical PGD2 challenge in prostaglandin-receptor knockout mice

Topical PGD2 inhibited mouse hair lengthening in susceptible comparator genotypes, while Gpr44-null mice were resistant. Ptgdr-null and Ptgds-null mice remained sensitive. This tests receptor dependence of an induced growth-inhibition endpoint. Topical treatment did not induce premature catagen and does not establish reversal of established human AGA by GPR44 blockade.

Species

Mouse

Genotype

Gpr44-null, Ptgdr-null, Ptgds-null and comparator mice

Publication

PMID:22440736

Pathograph links

PGD2-Associated Hair Growth Inhibition perturbs fidelity: moderate observes: cellular The genotype comparison tests Gpr44 dependence of the topical response.

Limitations: Mouse induced endpoint; no human receptor knockout, clinical regrowth or obligatory catagen sequence.

Show evidence (1 reference)

PMID:22440736 SUPPORT PRIMARY RESULT Model Organism

"Whereas Ptgds and Ptgdr knockout mice were both susceptible to the inhibition of hair lengthening, Gpr44 null mice were resistant to the inhibitory effect of PGD2"

Topical-challenge resistance establishes Gpr44 dependence in mice, not a human receptor knockout or clinical rescue.

Show evidence (2 references)

PMID:22440736 SUPPORT PRIMARY RESULT Model Organism

"Whereas Ptgds and Ptgdr knockout mice were both susceptible to the inhibition of hair lengthening, Gpr44 null mice were resistant to the inhibitory effect of PGD2"

Topical-challenge resistance establishes Gpr44 dependence in mice, not a human receptor knockout or clinical rescue.

PMID:22440736 SUPPORT PRIMARY RESULT Model Organism

"Although we did not elicit premature catagen in mice treated topically with PGD2, we observed a negative effect on hair growth"

The investigators explicitly did not elicit early catagen with topical PGD2.

Recombinant IL6 injection during mouse anagen

Recombinant human IL6 injected into the mouse hypodermis during anagen caused early catagen. This is a cytokine perturbation of the hair cycle, distinct from the human follicle organ-culture proliferation experiment and from chronic androgenetic alopecia.

Species

Mouse

Publication

PMID:21881585

Pathograph links

Shortened Anagen perturbs fidelity: moderate observes: tissue The induced early catagen endpoint shortens the active-growth interval.

Limitations: Does not demonstrate that endogenous IL6 is necessary for human AGA or model its regional susceptibility.

Readouts

Duration of anagen after IL6 injection

Direction: DECREASED

Interpretation: Early catagen follows experimental cytokine exposure.

Show evidence (1 reference)

PMID:21881585 SUPPORT PRIMARY RESULT Model Organism

"Moreover, rhIL-6 injection into the hypodermis of mice during anagen caused premature onset of catagen."

The in-vivo cycle intervention is recombinant IL6 injection in mice.

Show evidence (1 reference)

PMID:21881585 SUPPORT PRIMARY RESULT Model Organism

"Moreover, rhIL-6 injection into the hypodermis of mice during anagen caused premature onset of catagen."

The in-vivo cycle intervention is recombinant IL6 injection in mice.

Show evidence (1 reference)

PMID:21881585 SUPPORT PRIMARY RESULT Model Organism

"Moreover, rhIL-6 injection into the hypodermis of mice during anagen caused premature onset of catagen."

The in-vivo cycle intervention is recombinant IL6 injection in mice.

{ }

Source YAML

click to show

name: Androgenetic Alopecia
creation_date: '2026-09-04T23:23:40Z'
category: Complex
disease_term:
  preferred_term: Androgenetic Alopecia
  term:
    id: MONDO:0005339
    label: androgenetic alopecia
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0007184
      label: alopecia, androgenetic, 1
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    mapping_justification: 'MONDO:0007184 is the OMIM locus term for androgenetic alopecia 1 (AGA1), the form of common baldness attributed to the androgen-receptor / EDA2R locus on Xq11-q12. It is not a distinct clinical disease: AGA1 is the X-linked susceptibility component of the same patterned, androgen-dependent hair loss that this entry curates, and the AR/EDA2R locus is the strongest single signal in every genome-wide study of the trait (PMID:15902657, PMID:18385763, PMID:28349362). This entry is therefore broader than the locus term, since it also carries the 20p11 signal and the several hundred autosomal loci, so the mapping is recorded as narrowMatch rather than exactMatch. The stub keyed on MONDO:0007184 is retired by this entry.'
parents:
- Skin Disease
- Hair Disorder
- Endocrine-Responsive Disorder
synonyms:
- AGA
- Androgenic alopecia
- Pattern hair loss
- Common baldness
- Male pattern hair loss
- Male pattern baldness
- MPHL
- Female pattern hair loss
- FPHL
- Alopecia androgenetica
- AGA1
description: Androgenetic alopecia is a common, polygenic disorder of progressive patterned scalp-hair thinning associated with follicular miniaturization. Male-pattern hair loss commonly affects frontotemporal and vertex scalp; female-pattern hair loss commonly causes central thinning with variable frontal accentuation. These distributions overlap between sexes. Local androgen signaling has strong support in male-pattern disease, while the contribution of androgens to female-pattern disease varies and remains incompletely resolved. Clinical severity, rate of change and psychosocial impact differ substantially between individuals.
notes: 'Scope: male- and female-pattern presentations overlap clinically, and this entry does not assume identical androgen dependence in all women. Polygenic susceptibility is not Mendelian maternal inheritance. Clinical metabolic and anxiety associations are retained without invented causal edges. Trichoscopic diameter variation and the peripilar sign remain unbound because no sufficiently specific HPO term was identified; their heterogeneous study percentages are not disease-level frequency bands.

  Evidence review consumed the actual matching Falcon report, all original cached abstracts, available full scientific bodies and source-specific independent audits. Primary experimental compartments, denominators and endpoint definitions take precedence over the report''s mechanistic extrapolations. The StatPearls chapter NBK430924 was mined for diagnosis, differentials, prognosis and care; its erroneous potassium-channel-blocker wording and categorical comorbidity claims were not adopted. No applicable GeneReviews chapter was found for this common polygenic disorder.

  The generated URL references retain their cache titles. They provide full bodies for the diagnostic S1 guideline (DOI 10.1111/j.1365-2133.2010.10011.x), treatment S3 guideline (PMID 29178529), low-dose oral minoxidil Delphi statement (PMID 39565602), oral-versus-topical minoxidil trial (PMID 38598226), Goren sulfotransferase study (DOI 10.1111/dth.12164), StatPearls chapter (PMID 28613674), and the 2025 EMA finasteride/dutasteride safety review. Canonical abstract-only duplicates are not needed to support their full-body claims. Some older mechanism studies remain abstract-limited despite sanctioned regeneration, and their unreported assay detail is not inferred.

  No conserved module conformance is asserted for regional androgen-dependent follicular miniaturization. The cultured senescence finding does not by itself establish the organismal aging module. Distinct scarring alopecias are differential diagnoses, not inevitable AGA progression.

  ClinicalTrials.gov APIv2 status and planned enrollment were checked on 2026-09-21 for all seven listed registrations. None had posted results; registered aims do not establish efficacy.'
inheritance:
- name: Polygenic Inheritance
  description: A polygenic, sex-limited, age-dependent trait rather than a Mendelian disease. Twin studies put the heritability of male pattern baldness near 0.8, pedigree heritability in UK Biobank is 0.62, and several hundred genome-wide significant loci are known. The classic observation that baldness follows the maternal line reflects the strongest single signal, which lies at the androgen receptor / EDA2R locus on the X chromosome and is therefore inherited from the mother; but the X-linked locus accounts for only a minority of the heritable variance and the 20p11 locus and hundreds of autosomal loci are inherited from either parent, so the mode of inheritance is recorded as polygenic, not X-linked.
  inheritance_term:
    preferred_term: Polygenic inheritance
    term:
      id: HP:0010982
      label: Polygenic inheritance
  evidence:
  - reference: PMID:30573740
    reference_title: Dissection of genetic variation and evidence for pleiotropy in male pattern baldness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here we show that MPB is strongly heritable and polygenic, with pedigree-heritability of 0.62 (SE = 0.03) estimated from close relatives, and SNP-heritability of 0.39 (SE = 0.01) from conventionally-unrelated males.
    explanation: The largest single-cohort analysis states the polygenic architecture directly and quantifies heritability from relatives and from SNPs.
  - reference: PMID:30573740
    reference_title: Dissection of genetic variation and evidence for pleiotropy in male pattern baldness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Early twin studies estimated the narrow-sense heritability (h2) on a scale of liability to be 0.817 (95%CI: 0.77–0.85).'
    explanation: The twin heritability of about 0.8 that the description cites, quoted from the introduction of the same paper because the original twin study (Nyholt 2003, PMID:14675213) has no abstract in PubMed.
  - reference: PMID:15902657
    reference_title: Genetic variation in the human androgen receptor gene is the major determinant of common early-onset androgenetic alopecia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The X-chromosomal location of AR stresses the importance of the maternal line in the inheritance of AGA.
    explanation: 'Gives the reason for the classic maternal-line observation without making the trait X-linked: the strongest locus is on the X chromosome.'
  - reference: PMID:28349362
    reference_title: 'Androgenetic alopecia: a review.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: A number of genes determine the predisposition for androgenetic alopecia in a polygenic fashion.
    explanation: A systematic review's summary statement of the polygenic mode.
has_subtypes:
- name: Male pattern hair loss
  display_name: Male pattern hair loss (Hamilton-Norwood pattern)
  subtype_term:
    preferred_term: Male pattern baldness
    term:
      id: MONDO:0800201
      label: baldness, male pattern
  description: Frontotemporal recession and vertex thinning commonly occur in men and are graded with the Hamilton-Norwood scale. The androgen mechanism and evidence for 5-alpha-reductase inhibition are strongest in this presentation. Pattern labels describe distribution rather than excluding a similar pattern in another sex.
  evidence:
  - reference: PMID:1188424
    reference_title: 'Male pattern baldness: classification and incidence.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This report establishes such a classification, and reports its use in determining the incidence of male pattern baldness at various ages in 1,000 white adult male subjects.
    explanation: The Norwood classification and its incidence survey.
    quote_role: PRIMARY_RESULT
  - reference: PMID:38610726
    reference_title: 'Trichoscopy of Androgenetic Alopecia: A Systematic Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Typically, hair thinning in the frontotemporal areas, the recession of the frontotemporal hairline and hair loss in the vertex area occur in male androgenetic alopecia (MAGA).
    explanation: States the distribution that defines the male pattern.
    quote_role: REVIEW_SYNTHESIS
- name: Female pattern hair loss
  display_name: Female pattern hair loss (Ludwig / Sinclair pattern)
  description: Central and crown thinning with widening of the part commonly occurs in women, including Ludwig-type diffuse thinning, frontal accentuation and less often Hamilton-type recession. The frontal hairline is often preserved but this is not universal. Most affected women have normal circulating androgen concentrations. The degree of androgen dependence is heterogeneous; a null 1-mg finasteride trial in postmenopausal women does not settle all doses or populations, and a small placebo-controlled spironolactone add-on trial is now available.
  evidence:
  - reference: PMID:921894
    reference_title: Classification of the types of androgenetic alopecia (common baldness) occurring in the female sex.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: To facilitate an early diagnosis (desirable in view of the therapeutic possibilities by means of antiandrogens) a classification of the stages of the common form (female type) of androgenetic alopecia in women is presented.
    explanation: The Ludwig classification that defines the female pattern.
    quote_role: PRIMARY_RESULT
  - reference: PMID:16382668
    reference_title: 'Female pattern hair loss and its relationship to permanent/cicatricial alopecia: a new perspective.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Female pattern hair loss (FPHL) is a common hair disorder of the central scalp.
    explanation: Locates the female pattern on the central scalp.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:11231244
    reference_title: Incidence of female androgenetic alopecia (female pattern alopecia).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Female androgenetic alopecia is quite common beginning in the late 20s and reaching its peak after 50 years of age.
    explanation: Age distribution from a survey of 1,006 Caucasian women.
    quote_role: PRIMARY_RESULT
pathophysiology:
- name: Polygenic Susceptibility
  biological_scale: MOLECULAR
  description: Common variants at the AR/EDA2R region and many autosomal loci are associated with male-pattern hair loss. The largest cited study analyzes self-reported severity in European men, and its conditional analysis ultimately retains 622 association signals. Candidate-gene mapping and pathway enrichment do not establish the molecular action of each allele, and male cohorts do not establish an identical architecture for female-pattern hair loss. The AR locus motivates an androgen-response hypothesis; other susceptibility routes remain unresolved.
  evidence:
  - reference: PMID:28272467
    reference_title: Meta-analysis identifies novel risk loci and yields systematic insights into the biology of male-pattern baldness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: The 63 loci explain ∼39% of the phenotypic variance in MPB and highlight several plausible candidate genes (FGF5, IRF4, DKK2) and pathways (melatonin signalling, adipogenesis) that are likely to be implicated in the key-pathophysiological features of MPB and may represent promising targets for the development of novel therapeutic options.
    explanation: The European early-onset case-control meta-analysis identifies susceptibility loci; its reported variance is a binary regression estimate, not universal penetrance.
  - reference: PMID:30573740
    reference_title: Dissection of genetic variation and evidence for pleiotropy in male pattern baldness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: 'Ultimately, the net product was 622 loci: 598 autosomal and 24 on the X-chromosome'
    explanation: The final conditional signal set is statistical and does not identify 622 experimentally established causal genes.
  genes:
  - preferred_term: AR
    term:
      id: hgnc:644
      label: AR
  - preferred_term: EDA2R
    term:
      id: hgnc:17756
      label: EDA2R
  - preferred_term: WNT10A
    term:
      id: hgnc:13829
      label: WNT10A
  - preferred_term: FGF5
    term:
      id: hgnc:3683
      label: FGF5
  - preferred_term: TWIST1
    term:
      id: hgnc:12428
      label: TWIST1
  downstream:
  - target: Regional Androgen Receptor Abundance
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Regulatory variation near AR is proposed to influence scalp receptor abundance, but the association studies do not establish allele-specific mediation.
    evidence:
    - reference: PMID:11231320
      reference_title: Polymorphism of the androgen receptor gene is associated with male pattern baldness.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Functional mutation in or near the androgen receptor gene may explain the reported high levels of expression of this gene in the balding scalp.
      explanation: The source proposes, rather than demonstrates, a genotype-to-expression bridge.
      directness: INDIRECT
  - target: Follicular Miniaturization
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Genetic susceptibility is associated with the clinical trait whose tissue hallmark is miniaturization; most intervening allele-to-follicle mechanisms remain untested.
    evidence:
    - reference: PMID:28272467
      reference_title: Meta-analysis identifies novel risk loci and yields systematic insights into the biology of male-pattern baldness.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: The 63 loci explain ∼39% of the phenotypic variance in MPB and highlight several plausible candidate genes (FGF5, IRF4, DKK2) and pathways (melatonin signalling, adipogenesis) that are likely to be implicated in the key-pathophysiological features of MPB and may represent promising targets for the development of novel therapeutic options.
      explanation: The European early-onset case-control meta-analysis identifies susceptibility loci; its reported variance is a binary regression estimate, not universal penetrance.
      directness: INDIRECT
    - reference: PMID:30573740
      reference_title: Dissection of genetic variation and evidence for pleiotropy in male pattern baldness.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: 'Ultimately, the net product was 622 loci: 598 autosomal and 24 on the X-chromosome'
      explanation: The final conditional signal set is statistical and does not identify 622 experimentally established causal genes.
      directness: INDIRECT
- name: Regional Androgen Receptor Abundance
  biological_scale: MOLECULAR
  description: Frontal follicles contained more androgen receptor than occipital follicles in a small paired study, with lower frontal abundance in women than men. Cultured dermal papilla cells from balding scalp also had higher receptor binding capacity than non-balding cells. These observations support regional sensitivity but do not prove a universal explanation of sex-specific patterns. Receptor localization is preparation-dependent; the evidence does not justify excluding androgen receptors from all follicular epithelium.
  evidence:
  - reference: PMID:9284093
    reference_title: Different levels of 5alpha-reductase type I and II, aromatase, and androgen receptor in hair follicles of women and men with androgenetic alopecia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Findings revealed that both women and men have higher levels of receptors and 5alpha-reductase type I and II in frontal hair follices than in occipital follicles, whereas higher levels of aromatase were found in their occipital follicles.
    explanation: Paired frontal/occipital follicle measurements in 12 women and 12 men establish regional abundance differences, not receptor absence elsewhere.
  - reference: PMID:9496234
    reference_title: Balding hair follicle dermal papilla cells contain higher levels of androgen receptors than those from non-balding scalp.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Balding cells contained significantly (P < 0.01) greater levels of androgen receptors (Bmax = 0.06 +/- 0.01 fmol/10(4) cells (mean +/- S.E.M.)) than those from non-balding scalp (0.04 +/- 0.001).
    explanation: Cultured dermal papilla cells retain androgen binding at both sites, with greater binding capacity in balding-derived cells.
  genes:
  - preferred_term: AR
    term:
      id: hgnc:644
      label: AR
  locations:
  - &id005
    preferred_term: scalp
    term:
      id: UBERON:0000403
      label: scalp
  - &id001
    preferred_term: hair follicle
    term:
      id: UBERON:0002073
      label: hair follicle
  downstream:
  - target: Dihydrotestosterone-Androgen Receptor Signaling
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Greater receptor availability may increase ligand-dependent signaling; ligand concentration, receptor occupancy and transcriptional context also contribute.
    evidence:
    - reference: PMID:9284093
      reference_title: Different levels of 5alpha-reductase type I and II, aromatase, and androgen receptor in hair follicles of women and men with androgenetic alopecia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Findings revealed that both women and men have higher levels of receptors and 5alpha-reductase type I and II in frontal hair follices than in occipital follicles, whereas higher levels of aromatase were found in their occipital follicles.
      explanation: Paired frontal/occipital follicle measurements in 12 women and 12 men establish regional abundance differences, not receptor absence elsewhere.
    - reference: PMID:9496234
      reference_title: Balding hair follicle dermal papilla cells contain higher levels of androgen receptors than those from non-balding scalp.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: Balding cells contained significantly (P < 0.01) greater levels of androgen receptors (Bmax = 0.06 +/- 0.01 fmol/10(4) cells (mean +/- S.E.M.)) than those from non-balding scalp (0.04 +/- 0.001).
      explanation: Cultured dermal papilla cells retain androgen binding at both sites, with greater binding capacity in balding-derived cells.
- name: Regional 5-Alpha-Reductase Abundance
  biological_scale: MOLECULAR
  description: The paired follicle study found higher type 1 and type 2 5-alpha-reductase levels in frontal than occipital samples from women and men. Higher occipital aromatase and sex-related differences were also reported. These are regional measurements in selected participants, not evidence that all unaffected follicles lack androgen metabolism.
  evidence:
  - reference: PMID:9284093
    reference_title: Different levels of 5alpha-reductase type I and II, aromatase, and androgen receptor in hair follicles of women and men with androgenetic alopecia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Findings revealed that both women and men have higher levels of receptors and 5alpha-reductase type I and II in frontal hair follices than in occipital follicles, whereas higher levels of aromatase were found in their occipital follicles.
    explanation: The study measures regional enzyme abundance, not a direct in-vivo steroid flux assay.
  genes:
  - preferred_term: SRD5A2
    term:
      id: hgnc:11285
      label: SRD5A2
  - preferred_term: SRD5A1
    term:
      id: hgnc:11284
      label: SRD5A1
  locations:
  - *id001
  downstream:
  - target: Local Dihydrotestosterone Production
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Regional enzyme abundance can alter conversion capacity through enzyme activity, but abundance alone does not quantify net DHT flux or clearance.
    evidence:
    - reference: PMID:9284093
      reference_title: Different levels of 5alpha-reductase type I and II, aromatase, and androgen receptor in hair follicles of women and men with androgenetic alopecia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Findings revealed that both women and men have higher levels of receptors and 5alpha-reductase type I and II in frontal hair follices than in occipital follicles, whereas higher levels of aromatase were found in their occipital follicles.
      explanation: The study measures regional enzyme abundance, not a direct in-vivo steroid flux assay.
- name: Local Dihydrotestosterone Production
  biological_scale: MOLECULAR
  description: 5-alpha-reductases convert testosterone to the more potent androgen dihydrotestosterone within the follicular environment. Dermal papilla metabolism is implicated, while type 2 enzyme is also described in outer root sheath tissue. Human endocrine observations and DHT-lowering treatment support an important role in male-pattern disease. Normal circulating androgen concentrations can coexist with local susceptibility; this does not imply every patient has the same steroid profile.
  evidence:
  - reference: PMID:12213548
    reference_title: Molecular mechanisms of androgenetic alopecia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Conversion of testosterone to DHT within the dermal papilla plays a central role, while androgen-regulated factors deriving from dermal papilla cells are believed to influence growth of other components of the hair follicle.
    explanation: The review places local conversion in the follicular androgen mechanism; it is not a direct flux measurement in every follicular compartment.
  - reference: PMID:12573818
    reference_title: Androgens and alopecia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Observations in both eunuchs, who have low levels of testicular androgens, and males with genetic 5alpha-reductase (5alphaR) deficiency, who have low levels of dihydrotestosterone (DHT), implicate DHT as a key androgen in the pathogenesis of MPHL in men.
    explanation: Human endocrine observations support the importance of DHT in male-pattern hair loss without establishing a universal female mechanism.
  genes:
  - preferred_term: SRD5A2
    term:
      id: hgnc:11285
      label: SRD5A2
  - preferred_term: SRD5A1
    term:
      id: hgnc:11284
      label: SRD5A1
  locations:
  - *id001
  - &id002
    preferred_term: dermal papilla
    term:
      id: UBERON:0000412
      label: dermal papilla
  molecular_functions:
  - preferred_term: 3-oxo-5-alpha-steroid 4-dehydrogenase activity
    term:
      id: GO:0003865
      label: 3-oxo-5-alpha-steroid 4-dehydrogenase activity
    modifier: INCREASED
  biological_processes:
  - preferred_term: androgen metabolic process
    term:
      id: GO:0008209
      label: androgen metabolic process
    modifier: INCREASED
  downstream:
  - target: Dihydrotestosterone-Androgen Receptor Signaling
    causal_link_type: DIRECT
    description: Locally available DHT binds the androgen receptor. This ligand-receptor step is direct; downstream follicular responses depend on cell context.
    evidence:
    - reference: PMID:12213548
      reference_title: Molecular mechanisms of androgenetic alopecia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: REVIEW_SYNTHESIS
      snippet: androgen-dependent processes are predominantly due to the binding of dihydrotestosterone (DHT) to the androgen receptor (AR).
      explanation: The review describes the molecular ligand-receptor interaction rather than a patient outcome.
- name: Dihydrotestosterone-Androgen Receptor Signaling
  biological_scale: MOLECULAR
  description: Androgen-responsive dermal papilla cells can relay growth-inhibitory signals to follicular keratinocytes. Human coculture evidence includes an AR-transfected preparation that restored responsiveness lost during culture; macaque coculture shows antagonist-sensitive inhibition. These experiments support a paracrine route while leaving its quantitative contribution in patients unresolved. Androgens stimulate growth at other body sites, so signaling consequences depend on follicular context.
  evidence:
  - reference: PMID:12397096
    reference_title: 'Androgen-inducible TGF-beta1 from balding dermal papilla cells inhibits epithelial cell growth: a clue to understand paradoxical effects of androgen on human hair growth.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: In this modified coculture, androgen significantly suppressed the growth of KCs by approximately 50%, indicating that overexpression of AR can restore the responsiveness of the DPCs to androgen in vivo.
    explanation: Androgen inhibition required AR-transfected human dermal papilla cells in this assay; native cultured cells initially lacked a significant response.
  - reference: PMID:8977424
    reference_title: Inhibition of hair growth by testosterone in the presence of dermal papilla cells from the frontal bald scalp of the postpubertal stumptailed macaque.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Furthermore, RU 58841, an androgen receptor blocker, antagonized this testosterone-elicited inhibition.
    explanation: An AR blocker antagonized testosterone-dependent inhibition in macaque dermal-papilla/outer-root-sheath coculture.
  genes:
  - preferred_term: AR
    term:
      id: hgnc:644
      label: AR
  cell_types:
  - &id003
    preferred_term: hair follicle dermal papilla cell of scalp
    term:
      id: CL:2000083
      label: hair follicle dermal papilla cell of scalp
  locations:
  - *id002
  biological_processes:
  - preferred_term: androgen receptor signaling pathway
    term:
      id: GO:0030521
      label: androgen receptor signaling pathway
    modifier: INCREASED
  downstream:
  - target: Increased TGF-Beta1 Secretion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Androgen exposure increases TGF-beta1 secretion in the AR-transfected dermal papilla preparation; the intervening regulatory steps are not resolved.
    evidence:
    - reference: PMID:12397096
      reference_title: 'Androgen-inducible TGF-beta1 from balding dermal papilla cells inhibits epithelial cell growth: a clue to understand paradoxical effects of androgen on human hair growth.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: ELISA assays demonstrated that androgen treatment increased the secretion of both total and active TGF-beta1 in the conditioned medium.
      explanation: Androgen increased secreted TGF-beta1 in AR-transfected dermal papilla culture.
      directness: INDIRECT
  - target: Increased DKK1 Secretion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: DHT induces DKK1 expression and secretion in culture; the full receptor-to-transcription mechanism is not mapped by the cited assay.
    evidence:
    - reference: PMID:17657240
      reference_title: Dihydrotestosterone-inducible dickkopf 1 from balding dermal papilla cells causes apoptosis in follicular keratinocytes.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: DKK-1 messenger RNA is upregulated in 3-6 hours after 50-100 nM DHT treatment and ELISA showed that DKK-1 is secreted from DP cells in response to DHT.
      explanation: DHT exposure increased DKK1 transcript and secreted protein in cultured human dermal papilla cells.
      directness: INDIRECT
  - target: Increased IL6 Secretion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: DHT induces IL6 secretion in cultured balding-derived dermal papilla cells; this is not proof of obligatory cytokine mediation in patients.
    evidence:
    - reference: PMID:21881585
      reference_title: Dihydrotestosterone-inducible IL-6 inhibits elongation of human hair shafts by suppressing matrix cell proliferation and promotes regression of hair follicles in mice.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: IL-6 was upregulated 3 hours after 10-100 nM DHT treatment, and ELISA showed that IL-6 was secreted from balding DP cells in response to DHT.
      explanation: DHT exposure increased IL6 expression and secretion in balding-derived dermal papilla cultures.
      directness: INDIRECT
  - target: Reduced Canonical Wnt Signaling in Dermal Papilla Cells
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Androgen treatment alters the measured Wnt pathway readouts in dermal papilla cells; the intervening molecular interaction is unresolved.
    evidence:
    - reference: PMID:22283397
      reference_title: Hair follicle stem cell differentiation is inhibited through cross-talk between Wnt/β-catenin and androgen signalling in dermal papilla cells from patients with androgenetic alopecia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: Androgen treatment revealed a significant decrease in the cytoplasmic/total β-catenin protein ratio and upregulation of the activity of glycogen synthase kinase-3β in DPC, indicative of canonical Wnt pathway inhibition.
      explanation: The beta-catenin and GSK3beta measurements were in dermal papilla cells, not the follicular epithelium.
      directness: INDIRECT
- name: Increased TGF-Beta1 Secretion
  biological_scale: MOLECULAR
  description: Androgen exposure increased TGF-beta1 secretion in AR-transfected human dermal papilla cells. Neutralizing TGF-beta1 reversed growth inhibition of cocultured keratinocytes, supporting mediation within this preparation. The experiment does not establish that every untreated patient follicle uses this route to the same extent.
  evidence:
  - &id013
    reference: PMID:12397096
    reference_title: 'Androgen-inducible TGF-beta1 from balding dermal papilla cells inhibits epithelial cell growth: a clue to understand paradoxical effects of androgen on human hair growth.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: ELISA assays demonstrated that androgen treatment increased the secretion of both total and active TGF-beta1 in the conditioned medium.
    explanation: Androgen increased secreted TGF-beta1 in AR-transfected dermal papilla culture.
  cell_types:
  - *id003
  genes:
  - preferred_term: TGFB1
    term:
      id: hgnc:11766
      label: TGFB1
  biological_processes:
  - preferred_term: transforming growth factor beta1 production
    term:
      id: GO:0032905
      label: transforming growth factor beta1 production
    modifier: INCREASED
  downstream:
  - target: Reduced Follicular Keratinocyte Proliferation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: TGF-beta1-dependent signaling mediates growth suppression in the modified coculture; receptor signaling and cell-cycle control intervene between secretion and the population readout.
    evidence:
    - reference: PMID:12397096
      reference_title: 'Androgen-inducible TGF-beta1 from balding dermal papilla cells inhibits epithelial cell growth: a clue to understand paradoxical effects of androgen on human hair growth.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: Moreover, the neutralizing anti-TGF-beta1 antibody reversed the androgen-elicited growth inhibition of KCs in a dose-dependent manner.
      explanation: Antibody reversal supports TGF-beta1 mediation of the measured coculture inhibition.
- name: Increased DKK1 Secretion
  biological_scale: MOLECULAR
  description: DHT increased DKK1 expression and secretion in human dermal papilla cultures. DKK1 protein was also higher in bald than haired patient scalp. Neutralization and recombinant-protein experiments support keratinocyte growth inhibition and apoptosis in vitro; the paired scalp observation alone does not establish causality.
  evidence:
  - reference: PMID:17657240
    reference_title: Dihydrotestosterone-inducible dickkopf 1 from balding dermal papilla cells causes apoptosis in follicular keratinocytes.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: DKK-1 messenger RNA is upregulated in 3-6 hours after 50-100 nM DHT treatment and ELISA showed that DKK-1 is secreted from DP cells in response to DHT.
    explanation: DHT exposure increased DKK1 transcript and secreted protein in cultured human dermal papilla cells.
  - reference: PMID:17657240
    reference_title: Dihydrotestosterone-inducible dickkopf 1 from balding dermal papilla cells causes apoptosis in follicular keratinocytes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Moreover, immunoblotting showed that the DKK-1 level is up in the bald scalp compared with the haired scalp of patients with androgenetic alopecia.
    explanation: Patient scalp immunoblotting is an observational comparison distinct from the culture perturbations.
  genes:
  - preferred_term: DKK1
    term:
      id: hgnc:2891
      label: DKK1
  cell_types:
  - *id003
  downstream:
  - target: Reduced Follicular Keratinocyte Proliferation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: DKK1 neutralization reverses DHT-associated outer-root-sheath growth inhibition in coculture; the full route from secreted antagonist to cell-number change is not mapped.
    evidence:
    - reference: PMID:17657240
      reference_title: Dihydrotestosterone-inducible dickkopf 1 from balding dermal papilla cells causes apoptosis in follicular keratinocytes.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: A co-culture system using outer root sheath (ORS) keratinocytes and DP cells showed that DHT inhibits the growth of ORS cells, and neutralizing antibody against DKK-1 significantly reversed the growth inhibition of ORS cells.
      explanation: Neutralization supplies experimental mediation evidence in outer-root-sheath coculture.
      directness: INDIRECT
  - target: Increased Follicular Keratinocyte Apoptosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Recombinant DKK1 induces apoptosis in cultured outer-root-sheath cells. The experiment does not isolate every intracellular intermediate.
    evidence:
    - reference: PMID:17657240
      reference_title: Dihydrotestosterone-inducible dickkopf 1 from balding dermal papilla cells causes apoptosis in follicular keratinocytes.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: Also, recombinant human DKK-1 inhibited the growth of ORS cells and triggered apoptotic cell death.
      explanation: The apoptosis experiment is performed in cultured human outer-root-sheath cells.
      directness: INDIRECT
- name: Increased IL6 Secretion
  biological_scale: MOLECULAR
  description: DHT increased IL6 secretion in balding-derived dermal papilla cultures. Recombinant IL6 suppressed matrix-cell proliferation and shaft elongation in human follicle organ culture; injection during mouse anagen induced early catagen. Human organ culture and mouse cycle effects are distinct findings, not a demonstrated universal patient sequence.
  evidence:
  - reference: PMID:21881585
    reference_title: Dihydrotestosterone-inducible IL-6 inhibits elongation of human hair shafts by suppressing matrix cell proliferation and promotes regression of hair follicles in mice.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: IL-6 was upregulated 3 hours after 10-100 nM DHT treatment, and ELISA showed that IL-6 was secreted from balding DP cells in response to DHT.
    explanation: DHT exposure increased IL6 expression and secretion in balding-derived dermal papilla cultures.
  genes:
  - preferred_term: IL6
    term:
      id: hgnc:6018
      label: IL6
  cell_types:
  - *id003
  biological_processes:
  - preferred_term: interleukin-6 production
    term:
      id: GO:0032635
      label: interleukin-6 production
    modifier: INCREASED
  downstream:
  - target: Reduced Follicular Keratinocyte Proliferation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: IL6 receptor signaling and downstream cell-cycle regulation connect recombinant cytokine exposure to reduced matrix proliferation in organ culture.
    evidence:
    - reference: PMID:21881585
      reference_title: Dihydrotestosterone-inducible IL-6 inhibits elongation of human hair shafts by suppressing matrix cell proliferation and promotes regression of hair follicles in mice.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: Recombinant human IL-6 (rhIL-6) inhibited hair shaft elongation and suppressed proliferation of matrix cells in cultured human hair follicles.
      explanation: Recombinant cytokine suppresses matrix proliferation and elongation in human follicle culture.
  - target: Shortened Anagen
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Injected recombinant IL6 induces premature catagen in mice. Its contribution to shortened anagen in human AGA remains an experimental extrapolation.
    evidence:
    - reference: PMID:21881585
      reference_title: Dihydrotestosterone-inducible IL-6 inhibits elongation of human hair shafts by suppressing matrix cell proliferation and promotes regression of hair follicles in mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: Moreover, rhIL-6 injection into the hypodermis of mice during anagen caused premature onset of catagen.
      explanation: The cycle-transition intervention is in mice, not a clinical IL6 perturbation.
      directness: INDIRECT
- name: Reduced Canonical Wnt Signaling in Dermal Papilla Cells
  biological_scale: MOLECULAR
  description: Androgen-treated dermal papilla cells showed a lower cytoplasmic-to-total beta-catenin ratio and increased GSK3beta activity, interpreted as canonical Wnt inhibition. Wnt activation restored their ability to induce keratin expression in cocultured follicular cells. The measured signaling compartment is dermal papilla; this is separate from the reduced marker-defined progenitor populations observed in patient scalp.
  evidence:
  - &id014
    reference: PMID:22283397
    reference_title: Hair follicle stem cell differentiation is inhibited through cross-talk between Wnt/β-catenin and androgen signalling in dermal papilla cells from patients with androgenetic alopecia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Androgen treatment revealed a significant decrease in the cytoplasmic/total β-catenin protein ratio and upregulation of the activity of glycogen synthase kinase-3β in DPC, indicative of canonical Wnt pathway inhibition.
    explanation: The beta-catenin and GSK3beta measurements were in dermal papilla cells, not the follicular epithelium.
  cell_types:
  - *id003
  biological_processes:
  - preferred_term: canonical Wnt signaling pathway
    term:
      id: GO:0060070
      label: canonical Wnt signaling pathway
    modifier: DECREASED
  downstream:
  - target: Impaired Follicular Epithelial Differentiation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The rescue supports a Wnt-dependent contribution to dermal-papilla induction of epithelial differentiation; the complete paracrine relay is unresolved.
    evidence:
    - reference: PMID:22283397
      reference_title: Hair follicle stem cell differentiation is inhibited through cross-talk between Wnt/β-catenin and androgen signalling in dermal papilla cells from patients with androgenetic alopecia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: Wnt signalling activation restored the ability of androgen-treated DPC to induce differentiation.
      explanation: Wnt activation rescues the differentiation-inducing activity of androgen-treated dermal papilla cells in coculture.
      directness: INDIRECT
- name: Impaired Follicular Epithelial Differentiation
  biological_scale: CELLULAR
  description: Androgen-treated dermal papilla cells had reduced ability to induce hair keratin expression in cocultured follicular stem-cell preparations, restored by Wnt activation. This differentiation readout does not demonstrate a lineage-conversion block in living patient follicles.
  evidence:
  - &id015
    reference: PMID:22283397
    reference_title: Hair follicle stem cell differentiation is inhibited through cross-talk between Wnt/β-catenin and androgen signalling in dermal papilla cells from patients with androgenetic alopecia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Wnt signalling activation restored the ability of androgen-treated DPC to induce differentiation.
    explanation: Wnt activation rescues the differentiation-inducing activity of androgen-treated dermal papilla cells in coculture.
  cell_types:
  - &id004
    preferred_term: hair follicular keratinocyte
    term:
      id: CL:2000092
      label: hair follicular keratinocyte
  locations:
  - *id001
  downstream:
  - target: Follicular Miniaturization
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reduced epithelial differentiation is a candidate contributor to diminished follicle output, but culture rescue does not establish the complete mechanism of patient miniaturization.
    evidence:
    - reference: PMID:22283397
      reference_title: Hair follicle stem cell differentiation is inhibited through cross-talk between Wnt/β-catenin and androgen signalling in dermal papilla cells from patients with androgenetic alopecia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: Wnt signalling activation restored the ability of androgen-treated DPC to induce differentiation.
      explanation: Wnt activation rescues the differentiation-inducing activity of androgen-treated dermal papilla cells in coculture.
      directness: INDIRECT
- name: Reduced Follicular Keratinocyte Proliferation
  biological_scale: CELLULAR
  description: TGF-beta1-dependent coculture inhibition and recombinant IL6 effects support reduced epithelial growth in experimental follicular systems. These assays use different cell preparations and do not establish a single obligatory inhibitory cocktail in patients.
  evidence:
  - reference: PMID:12397096
    reference_title: 'Androgen-inducible TGF-beta1 from balding dermal papilla cells inhibits epithelial cell growth: a clue to understand paradoxical effects of androgen on human hair growth.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Moreover, the neutralizing anti-TGF-beta1 antibody reversed the androgen-elicited growth inhibition of KCs in a dose-dependent manner.
    explanation: Growth inhibition is measured in the AR-transfected dermal-papilla/keratinocyte preparation.
  - reference: PMID:21881585
    reference_title: Dihydrotestosterone-inducible IL-6 inhibits elongation of human hair shafts by suppressing matrix cell proliferation and promotes regression of hair follicles in mice.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Recombinant human IL-6 (rhIL-6) inhibited hair shaft elongation and suppressed proliferation of matrix cells in cultured human hair follicles.
    explanation: Recombinant cytokine suppresses matrix proliferation and elongation in human follicle culture.
  cell_types:
  - *id004
  biological_processes:
  - preferred_term: hair follicle cell proliferation
    term:
      id: GO:0071335
      label: hair follicle cell proliferation
    modifier: DECREASED
  downstream:
  - target: Follicular Miniaturization
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reduced epithelial growth could limit follicular output; the experiments do not show that this readout alone produces the chronic human tissue phenotype.
    evidence:
    - reference: PMID:12397096
      reference_title: 'Androgen-inducible TGF-beta1 from balding dermal papilla cells inhibits epithelial cell growth: a clue to understand paradoxical effects of androgen on human hair growth.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: Moreover, the neutralizing anti-TGF-beta1 antibody reversed the androgen-elicited growth inhibition of KCs in a dose-dependent manner.
      explanation: Growth inhibition is measured in the AR-transfected dermal-papilla/keratinocyte preparation.
      directness: INDIRECT
    - reference: PMID:21881585
      reference_title: Dihydrotestosterone-inducible IL-6 inhibits elongation of human hair shafts by suppressing matrix cell proliferation and promotes regression of hair follicles in mice.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: Recombinant human IL-6 (rhIL-6) inhibited hair shaft elongation and suppressed proliferation of matrix cells in cultured human hair follicles.
      explanation: Recombinant cytokine suppresses matrix proliferation and elongation in human follicle culture.
      directness: INDIRECT
- name: Increased Follicular Keratinocyte Apoptosis
  biological_scale: CELLULAR
  description: Recombinant DKK1 induced outer-root-sheath keratinocyte apoptosis, and DKK1 neutralization countered DHT-associated cell death in cultured follicles. This provides an experimental epithelial-injury route; it does not demonstrate loss of the KRT15-defined human bulge compartment.
  evidence:
  - reference: PMID:17657240
    reference_title: Dihydrotestosterone-inducible dickkopf 1 from balding dermal papilla cells causes apoptosis in follicular keratinocytes.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Also, recombinant human DKK-1 inhibited the growth of ORS cells and triggered apoptotic cell death.
    explanation: Recombinant DKK1 induces apoptosis in cultured outer-root-sheath cells; this is not a patient lineage-depletion measurement.
  cell_types:
  - preferred_term: outer root sheath cell
    term:
      id: CL:0002561
      label: outer root sheath cell
  biological_processes:
  - preferred_term: keratinocyte apoptotic process
    term:
      id: GO:0097283
      label: keratinocyte apoptotic process
    modifier: INCREASED
  downstream:
  - target: Follicular Miniaturization
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Experimental epithelial apoptosis may contribute to reduced follicle output, but its necessity and quantitative role in patient miniaturization are unresolved.
    evidence:
    - reference: PMID:17657240
      reference_title: Dihydrotestosterone-inducible dickkopf 1 from balding dermal papilla cells causes apoptosis in follicular keratinocytes.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: Also, recombinant human DKK-1 inhibited the growth of ORS cells and triggered apoptotic cell death.
      explanation: Recombinant DKK1 induces apoptosis in cultured outer-root-sheath cells; this is not a patient lineage-depletion measurement.
      directness: INDIRECT
- name: Prostaglandin D2 Elevation in Bald Scalp
  biological_scale: MOLECULAR
  description: PTGDS expression and PGD2 were elevated in bald compared with haired scalp from selected male hair-transplant donors. The patient observations are cross-sectional. An androgen-to-PTGDS bridge in human scalp was not directly tested, and the multiple-prostanoid K14-Ptgs2 mouse does not establish selective PGD2 sufficiency.
  evidence:
  - reference: PMID:22440736
    reference_title: Prostaglandin D2 inhibits hair growth and is elevated in bald scalp of men with androgenetic alopecia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: We show that prostaglandin D(2) synthase (PTGDS) is elevated at the mRNA and protein levels in bald scalp compared to haired scalp of men with AGA.
    explanation: Paired scalp measurements show elevated synthase expression in selected male transplant patients.
  genes:
  - preferred_term: PTGDS
    term:
      id: hgnc:9592
      label: PTGDS
  locations:
  - *id005
  downstream:
  - target: PGD2-Associated Hair Growth Inhibition
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Elevated tissue PGD2 motivates a receptor-mediated inhibitory route supported by organ culture and mouse perturbation, but the human concentration-response and receptor-necessity bridge remain unproven.
    evidence:
    - reference: PMID:22440736
      reference_title: Prostaglandin D2 inhibits hair growth and is elevated in bald scalp of men with androgenetic alopecia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: We show that PGD(2) inhibits hair growth in explanted human hair follicles and when applied topically to mice.
      explanation: The paper includes growth inhibition of explanted human follicles; mouse topical experiments are assessed separately.
- name: PGD2-Associated Hair Growth Inhibition
  biological_scale: CELLULAR
  description: PGD2 inhibited elongation of terminal human face/brow follicles in organ culture and hair lengthening after topical mouse exposure. Gpr44-null mice resisted the topical effect, whereas Ptgdr-null mice remained sensitive. Human receptor involvement was inferred from agonist correlations. Topical PGD2 did not elicit premature mouse catagen, so growth inhibition is not equated with an established regression or miniaturization sequence.
  evidence:
  - &id016
    reference: PMID:22440736
    reference_title: Prostaglandin D2 inhibits hair growth and is elevated in bald scalp of men with androgenetic alopecia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: We show that PGD(2) inhibits hair growth in explanted human hair follicles and when applied topically to mice.
    explanation: The paper includes growth inhibition of explanted human follicles; mouse topical experiments are assessed separately.
  - &id009
    reference: PMID:22440736
    reference_title: Prostaglandin D2 inhibits hair growth and is elevated in bald scalp of men with androgenetic alopecia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: Whereas Ptgds and Ptgdr knockout mice were both susceptible to the inhibition of hair lengthening, Gpr44 null mice were resistant to the inhibitory effect of PGD2
    explanation: Topical-challenge resistance establishes Gpr44 dependence in mice, not a human receptor knockout or clinical rescue.
  locations:
  - *id001
  downstream:
  - target: Patterned non-scarring scalp hair loss
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Experimental inhibition of hair output is a plausible contributor to visible thinning, but no intervention in this study establishes PGD2-mediated clinical hair loss or regrowth in patients.
    evidence:
    - reference: PMID:22440736
      reference_title: Prostaglandin D2 inhibits hair growth and is elevated in bald scalp of men with androgenetic alopecia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: We show that PGD(2) inhibits hair growth in explanted human hair follicles and when applied topically to mice.
      explanation: The paper includes growth inhibition of explanted human follicles; mouse topical experiments are assessed separately.
      directness: INDIRECT
- name: Reduced Marker-Defined Follicular Progenitor Compartments
  biological_scale: CELLULAR
  description: 'Paired bald frontal and haired occipital scalp showed lower CD200-high/ITGA6-high and CD34-high cell proportions, while KRT15-high proportions were similar. Assay subsets were small: eight paired KRT15 comparisons, nine CD200/ITGA6 comparisons and three CD34 comparisons. Preserved marker fractions do not establish normal absolute stem-cell numbers or regenerative function. A stem-to-progenitor conversion defect is inferred, and the source explicitly leaves primary versus secondary causation unresolved.'
  evidence:
  - reference: PMID:21206086
    reference_title: Bald scalp in men with androgenetic alopecia retains hair follicle stem cells but lacks CD200-rich and CD34-positive hair follicle progenitor cells.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: On average, the percentage of KRT15hicells was the same in bald and haired scalp
    explanation: The paired KRT15 assay measures similar cell proportions, not absolute normal stem-cell numbers or functional rescue.
  - reference: PMID:21206086
    reference_title: Bald scalp in men with androgenetic alopecia retains hair follicle stem cells but lacks CD200-rich and CD34-positive hair follicle progenitor cells.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: These findings support the notion that a defect in conversion of hair follicle stem cells to progenitor cells plays a role in the pathogenesis of AGA.
    explanation: Cross-sectional marker differences motivate a conversion hypothesis; human lineage tracing and conversion-rate measurements were not performed.
  - reference: PMID:21206086
    reference_title: Bald scalp in men with androgenetic alopecia retains hair follicle stem cells but lacks CD200-rich and CD34-positive hair follicle progenitor cells.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Whether the decrease in these cells is a primary or secondary event in AGA remains to be determined
    explanation: The study explicitly limits the causal interpretation of reduced progenitor-marker populations.
  cell_types:
  - *id004
  locations:
  - preferred_term: hair follicle bulge
    term:
      id: UBERON:0005975
      label: hair follicle bulge
  downstream:
  - target: Follicular Miniaturization
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reduced progenitor compartments could limit epithelial renewal, but the paired observational study does not establish temporal direction or a necessary conversion block.
    evidence:
    - reference: PMID:21206086
      reference_title: Bald scalp in men with androgenetic alopecia retains hair follicle stem cells but lacks CD200-rich and CD34-positive hair follicle progenitor cells.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: These findings support the notion that a defect in conversion of hair follicle stem cells to progenitor cells plays a role in the pathogenesis of AGA.
      explanation: Cross-sectional marker differences motivate a conversion hypothesis; human lineage tracing and conversion-rate measurements were not performed.
      directness: INDIRECT
- name: Premature Senescence of Cultured Dermal Papilla Cells
  biological_scale: CELLULAR
  description: Balding-derived dermal papilla cultures displayed slower growth and senescence-associated morphology, beta-galactosidase and p16/pRB changes. This is a culture phenotype and a proposed contributor to reduced regenerative capacity; the study does not establish androgen-triggered senescence or dermal-papilla depletion in living patients.
  evidence:
  - reference: PMID:17989730
    reference_title: Premature senescence of balding dermal papilla cells in vitro is associated with p16(INK4a) expression.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Premature senescence of balding DPC in vitro in association with expression of p16(INK4a)/pRB suggests that balding DPC are sensitive to environmental stress and identifies alternative pathways that could lead to novel therapeutic strategies for treatment of AGA.
    explanation: The senescence phenotype is measured in cultured balding-derived dermal papilla cells, with no demonstrated in-vivo cell-loss sequence.
  cell_types:
  - *id003
  biological_processes:
  - preferred_term: cellular senescence
    term:
      id: GO:0090398
      label: cellular senescence
    modifier: INCREASED
  downstream:
  - target: Follicular Miniaturization
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: A reduced ability of dermal papilla cells to maintain their population is a proposed route to smaller follicles; in-vivo mediation remains untested.
    evidence:
    - reference: PMID:17989730
      reference_title: Premature senescence of balding dermal papilla cells in vitro is associated with p16(INK4a) expression.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: Premature senescence of balding DPC in vitro in association with expression of p16(INK4a)/pRB suggests that balding DPC are sensitive to environmental stress and identifies alternative pathways that could lead to novel therapeutic strategies for treatment of AGA.
      explanation: The senescence phenotype is measured in cultured balding-derived dermal papilla cells, with no demonstrated in-vivo cell-loss sequence.
      directness: INDIRECT
- name: Shortened Anagen
  biological_scale: TISSUE
  description: AGA is associated with a shorter active hair-growth phase and an altered anagen-to-telogen balance. Less time in anagen can limit shaft length and the number of actively growing hairs. Shortened cycling alone is not sufficient to explain all observed miniaturization, and no obligatory anagen-to-miniaturization edge is asserted.
  evidence:
  - reference: PMID:41606541
    reference_title: 'Risk factors for androgenetic alopecia: a systematic review and meta-analysis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Androgenetic alopecia (AGA), the most prevalent type of hair loss, is characterized by progressive hair follicle miniaturization and disruption of the hair growth cycle, with a shortened anagen phase and an extended telogen phase, eventually leading to baldness [1].
    explanation: The review describes the clinical hair-cycle phenotype; this sentence is background synthesis, not a new longitudinal cycle experiment.
  locations:
  - *id001
  downstream:
  - target: Fine, short vellus-like scalp hairs
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Reduced time for shaft growth contributes to short hairs; shaft caliber additionally depends on follicle size.
    evidence:
    - reference: PMID:41606541
      reference_title: 'Risk factors for androgenetic alopecia: a systematic review and meta-analysis.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Androgenetic alopecia (AGA), the most prevalent type of hair loss, is characterized by progressive hair follicle miniaturization and disruption of the hair growth cycle, with a shortened anagen phase and an extended telogen phase, eventually leading to baldness [1].
      explanation: The review describes the clinical hair-cycle phenotype; this sentence is background synthesis, not a new longitudinal cycle experiment.
  - target: Patterned non-scarring scalp hair loss
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: A smaller fraction of actively growing follicles can reduce visible hair coverage through altered cycle occupancy.
    evidence:
    - reference: PMID:41606541
      reference_title: 'Risk factors for androgenetic alopecia: a systematic review and meta-analysis.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Androgenetic alopecia (AGA), the most prevalent type of hair loss, is characterized by progressive hair follicle miniaturization and disruption of the hair growth cycle, with a shortened anagen phase and an extended telogen phase, eventually leading to baldness [1].
      explanation: The review describes the clinical hair-cycle phenotype; this sentence is background synthesis, not a new longitudinal cycle experiment.
- name: Prolonged Kenogen
  biological_scale: TISSUE
  description: A longer interval between shedding and renewed anagen growth may leave more follicles temporarily empty. This hair-cycle contribution to reduced density is distinct from a reduction in follicle size and is not quantified for all patients.
  evidence:
  - reference: PMID:38610726
    reference_title: 'Trichoscopy of Androgenetic Alopecia: A Systematic Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: The reduction in hair density may also be attributed to the extension of the kenogen phase, occurring concurrently with the miniaturization process of the hair follicle in the frontoparietal region [4].
    explanation: The review proposes longer empty-follicle intervals as an additional contributor to reduced density.
  locations:
  - *id001
  downstream:
  - target: Patterned non-scarring scalp hair loss
    causal_link_type: DIRECT
    description: Longer empty intervals reduce the number of visible shafts at a given time, without requiring permanent follicle loss.
    evidence:
    - reference: PMID:38610726
      reference_title: 'Trichoscopy of Androgenetic Alopecia: A Systematic Review.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: The reduction in hair density may also be attributed to the extension of the kenogen phase, occurring concurrently with the miniaturization process of the hair follicle in the frontoparietal region [4].
      explanation: The review proposes longer empty-follicle intervals as an additional contributor to reduced density.
- name: Follicular Miniaturization
  biological_scale: TISSUE
  description: Affected scalp contains smaller follicles producing finer, shorter shafts, with fewer terminal hairs and increased vellus-like hairs and fibrous streamers. Miniaturization is a tissue hallmark of nonscarring AGA. A reduction in dermal-papilla cell number has been proposed as a mediator, but is not established by the cited conceptual paper. Perifollicular fibrosis and distinct scarring alopecias must not be treated as inevitable progression of this process.
  evidence:
  - reference: PMID:8496421
    reference_title: Diagnostic and predictive value of horizontal sections of scalp biopsy specimens in male pattern androgenetic alopecia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: The diagnosis of MPAA was confirmed by finding decreased terminal hairs and increased stelae and vellus hairs.
    explanation: Horizontal biopsy sections show fewer terminal hairs and more vellus hairs and stelae in a selected male-pattern series.
  - reference: PMID:11511857
    reference_title: Possible mechanisms of miniaturization during androgenetic alopecia or pattern hair loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: It is hypothesized that the miniaturization seen with pattern hair loss may be the direct result of reduction in the cell number and, hence, size of the dermal papilla.
    explanation: The source explicitly presents papilla cell-number reduction as a hypothesis.
  locations:
  - *id001
  cell_types:
  - preferred_term: hair follicle cell
    term:
      id: CL:0002559
      label: hair follicle cell
  downstream:
  - target: Patterned non-scarring scalp hair loss
    causal_link_type: DIRECT
    description: Smaller follicles produce fine shafts and reduced visible coverage; the distribution reflects which scalp regions are affected.
    evidence:
    - reference: PMID:8496421
      reference_title: Diagnostic and predictive value of horizontal sections of scalp biopsy specimens in male pattern androgenetic alopecia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: The diagnosis of MPAA was confirmed by finding decreased terminal hairs and increased stelae and vellus hairs.
      explanation: Horizontal biopsy sections show fewer terminal hairs and more vellus hairs and stelae in a selected male-pattern series.
  - target: Fine, short vellus-like scalp hairs
    causal_link_type: DIRECT
    description: Smaller follicles produce fine shafts and reduced visible coverage; the distribution reflects which scalp regions are affected.
    evidence:
    - reference: PMID:8496421
      reference_title: Diagnostic and predictive value of horizontal sections of scalp biopsy specimens in male pattern androgenetic alopecia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: The diagnosis of MPAA was confirmed by finding decreased terminal hairs and increased stelae and vellus hairs.
      explanation: Horizontal biopsy sections show fewer terminal hairs and more vellus hairs and stelae in a selected male-pattern series.
  - target: Hair diameter variability on trichoscopy
    causal_link_type: DIRECT
    description: Smaller follicles produce fine shafts and reduced visible coverage; the distribution reflects which scalp regions are affected.
    evidence:
    - reference: PMID:8496421
      reference_title: Diagnostic and predictive value of horizontal sections of scalp biopsy specimens in male pattern androgenetic alopecia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: The diagnosis of MPAA was confirmed by finding decreased terminal hairs and increased stelae and vellus hairs.
      explanation: Horizontal biopsy sections show fewer terminal hairs and more vellus hairs and stelae in a selected male-pattern series.
  - target: Frontotemporal hairline recession and vertex thinning
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Regional follicular susceptibility determines the distribution of miniaturization. These clinical patterns overlap between sexes rather than defining exclusive mechanisms.
    evidence:
    - reference: PMID:9284093
      reference_title: Different levels of 5alpha-reductase type I and II, aromatase, and androgen receptor in hair follicles of women and men with androgenetic alopecia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Findings revealed that both women and men have higher levels of receptors and 5alpha-reductase type I and II in frontal hair follices than in occipital follicles, whereas higher levels of aromatase were found in their occipital follicles.
      explanation: Regional abundance differences support an anatomic susceptibility context, not a complete explanation of either pattern.
  - target: Diffuse central scalp thinning with preserved frontal hairline
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Regional follicular susceptibility determines the distribution of miniaturization. These clinical patterns overlap between sexes rather than defining exclusive mechanisms.
    evidence:
    - reference: PMID:9284093
      reference_title: Different levels of 5alpha-reductase type I and II, aromatase, and androgen receptor in hair follicles of women and men with androgenetic alopecia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Findings revealed that both women and men have higher levels of receptors and 5alpha-reductase type I and II in frontal hair follices than in occipital follicles, whereas higher levels of aromatase were found in their occipital follicles.
      explanation: Regional abundance differences support an anatomic susceptibility context, not a complete explanation of either pattern.
- name: Perifollicular Inflammation
  biological_scale: TISSUE
  description: Activated T cells, mast-cell degranulation and fibroblast activation were described around follicles in a small progressive-pattern biopsy series. Larger biopsy data associate inflammation with a lower observed minoxidil response. These cross-sectional findings do not determine whether inflammation precedes, follows or independently modifies miniaturization.
  evidence:
  - reference: PMID:1390168
    reference_title: 'Characterization of inflammatory infiltrates in male pattern alopecia: implications for pathogenesis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Immunohistochemically, control biopsies were devoid of follicular inflammation (n = 3), while transitional regions consistently showed the presence of activated T-cell infiltrates about the lower portions of follicular infundibula.
    explanation: Activated T-cell infiltration was observed in transitional scalp from three men and one woman, with three controls; it is not a universal AGA finding.
  - reference: PMID:8496421
    reference_title: Diagnostic and predictive value of horizontal sections of scalp biopsy specimens in male pattern androgenetic alopecia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: In MPAA with no significant inflammation, regrowth occurred in 77% of cases, versus 55% in cases with significant inflammation.
    explanation: In a 44-person treatment subset, observed regrowth was 77% without versus 55% with significant inflammation; this is not a randomized inflammatory intervention.
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  - preferred_term: mast cell
    term:
      id: CL:0000097
      label: mast cell
  locations:
  - *id001
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  downstream:
  - target: Perifollicular Fibrosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Inflammation may contribute to connective-tissue remodeling, but the biopsy associations do not isolate an inflammatory-to-fibrotic sequence.
    evidence:
    - reference: PMID:1390168
      reference_title: 'Characterization of inflammatory infiltrates in male pattern alopecia: implications for pathogenesis.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: This finding was associated with mast cell degranulation and fibroblast activation within the fibrous sheaths.
      explanation: Mast-cell degranulation and fibroblast activation accompany sheath changes; temporal causation was not tested.
      directness: INDIRECT
  - target: Peripilar sign on trichoscopy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Peripilar discoloration is associated with superficial perifollicular inflammation in trichoscopic literature, but is not a universal or individually definitive inflammatory marker.
    evidence:
    - reference: PMID:38610726
      reference_title: 'Trichoscopy of Androgenetic Alopecia: A Systematic Review.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: A conspicuous brown halo, also known as the peripilar sign, indicates perifollicular inflammation [13].
      explanation: This review associates the sign with perifollicular inflammation; frequency varies across included studies.
      directness: INDIRECT
- name: Perifollicular Fibrosis
  biological_scale: TISSUE
  description: Perifollicular sheath thickening and fibrosis can accompany AGA. Connective-tissue remodeling is a proposed modifier of follicular function, with unresolved causal direction. Follicular dropout in fibrosing alopecia in a pattern distribution represents a scarring differential diagnosis and is not established as the inevitable endpoint of nonscarring AGA.
  evidence:
  - reference: PMID:1390168
    reference_title: 'Characterization of inflammatory infiltrates in male pattern alopecia: implications for pathogenesis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: This finding was associated with mast cell degranulation and fibroblast activation within the fibrous sheaths.
    explanation: Mast-cell degranulation and fibroblast activation accompany sheath changes; temporal causation was not tested.
  - reference: PMID:12213548
    reference_title: Molecular mechanisms of androgenetic alopecia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Since the clinical success rate of treatment of AGA with modulators of androgen metabolism or hair growth promoters is limited, sustained microscopic follicular inflammation with connective tissue remodeling, eventually resulting in permanent hair loss, is considered a possible cofactor in the complex etiology of AGA.
    explanation: The review describes inflammation and remodeling as a possible cofactor, not an established obligatory cause.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  locations:
  - *id001
  biological_processes:
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: INCREASED
  downstream:
  - target: Follicular Miniaturization
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Sheath remodeling may impair normal cycling or follicular support, but its direction and necessity in AGA remain unresolved.
    evidence:
    - reference: PMID:1390168
      reference_title: 'Characterization of inflammatory infiltrates in male pattern alopecia: implications for pathogenesis.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Injury to follicular stem cell epithelium and/or thickening of adventitial sheaths may impair normal pilar cycling and result in hair loss.
      explanation: The authors propose effects on cycling and hair loss from the associated tissue changes.
      directness: INDIRECT
phenotypes:
- name: Patterned non-scarring scalp hair loss
  category: Dermatologic
  description: Progressive patterned thinning or loss of terminal scalp hair with preserved follicular openings. This is the defining clinical finding. Onset is usually after puberty, and the course varies between individuals; rapid diffuse shedding or loss of ostia warrants assessment for another or coexisting disorder.
  phenotype_term:
    preferred_term: Androgenetic (patterned) alopecia
    term:
      id: HP:0001596
      label: Alopecia
  frequency: OBLIGATE
  evidence:
  - reference: PMID:12213548
    reference_title: Molecular mechanisms of androgenetic alopecia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Androgenetic alopecia (AGA) is hereditary and androgen-dependent, progressive thinning of the scalp hair that follows a defined pattern.
    explanation: The defining description; obligate because it is the definition.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:38610726
    reference_title: 'Trichoscopy of Androgenetic Alopecia: A Systematic Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Androgenetic alopecia (AGA), also known as pattern hair loss, is the most common cause of non-scarring alopecia.
    explanation: Non-scarring, and the most common cause of it.
    quote_role: REVIEW_SYNTHESIS
- name: Frontotemporal hairline recession and vertex thinning
  category: Dermatologic
  subtype: Male pattern hair loss
  description: Frontotemporal recession and vertex thinning may enlarge and merge in a Hamilton-Norwood distribution. In a US community survey, the predominantly frontal variant was reported in 12% of all examined men, not 12% of AGA cases. The pattern is common in male presentations but is not exclusive to men.
  phenotype_term:
    preferred_term: Frontotemporal hairline recession
    term:
      id: HP:0002292
      label: Frontal balding
  evidence:
  - reference: PMID:38610726
    reference_title: 'Trichoscopy of Androgenetic Alopecia: A Systematic Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Typically, hair thinning in the frontotemporal areas, the recession of the frontotemporal hairline and hair loss in the vertex area occur in male androgenetic alopecia (MAGA).
    explanation: The male distribution.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:30573740
    reference_title: Dissection of genetic variation and evidence for pleiotropy in male pattern baldness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'The balding process is highly patterned, suggesting that MPB progression is induced by some ageing-associated program: from initial frontotemporal hairline recession to a more severe occipital horseshoe stage1.'
    explanation: The progression from recession to the horseshoe stage.
    quote_role: PRIMARY_RESULT
  - reference: PMID:9865198
    reference_title: Prevalence of male pattern hair loss in 18-49 year old men.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Twelve percent of the men were classified as having predominantly frontal baldness (type A variants).
    explanation: Frequency of the frontal-predominant variant in a community sample.
    quote_role: PRIMARY_RESULT
- name: Diffuse central scalp thinning with preserved frontal hairline
  category: Dermatologic
  subtype: Female pattern hair loss
  description: Widening of the central part and thinning over the crown characterize the Ludwig-type presentation, often with preservation of the frontal hairline. Female-pattern disease also includes frontal accentuation and less often a Hamilton-type pattern, so this finding is not obligatory in every affected woman.
  phenotype_term:
    preferred_term: Diffuse central scalp thinning (Ludwig pattern)
    term:
      id: HP:0002209
      label: Sparse scalp hair
  evidence:
  - reference: PMID:38610726
    reference_title: 'Trichoscopy of Androgenetic Alopecia: A Systematic Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In female androgenetic alopecia (FAGA), hair thinning occurs over the frontal and parietal areas of the scalp (Ludwig type)
    explanation: The female distribution.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:921894
    reference_title: Classification of the types of androgenetic alopecia (common baldness) occurring in the female sex.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The exceptionally observed male type of androgenetic alopecia can be classified according to Hamilton or to the modification of this classification proposed by Ebling & Rook.
    explanation: The male-type pattern is the exception in women, so the Ludwig pattern is the rule.
    quote_role: PRIMARY_RESULT
- name: Fine, short vellus-like scalp hairs
  category: Dermatologic
  description: Fine, short, vellus-like hairs arise in affected scalp as follicles miniaturize. A trichoscopy review reports a pooled vellus-hair frequency of 66.45% from 13 studies with 775 assessed patients, with heterogeneous detection methods. This is a study summary rather than a universal disease frequency, and vellus hairs also occur in normal scalp and other alopecias.
  phenotype_term:
    preferred_term: Vellus-like miniaturized scalp hair
    term:
      id: HP:0002213
      label: Fine hair
  evidence:
  - reference: PMID:11511857
    reference_title: Possible mechanisms of miniaturization during androgenetic alopecia or pattern hair loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In androgenetic alopecia, or pattern hair loss, follicles undergo miniaturization, shrinking from terminal to vellus-like hairs.
    explanation: The terminal-to-vellus conversion that produces the fine hair.
    quote_role: PRIMARY_RESULT
  - reference: PMID:38610726
    reference_title: 'Trichoscopy of Androgenetic Alopecia: A Systematic Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The most common features identified using trichoscopy included hair diameter variability (94.07% of patients), vellus hairs (66.45%) and the peripilar sign (43.27%).
    explanation: Vellus hairs in 66.45% of patients across 34 studies, which places the frequency in the FREQUENT band.
    quote_role: REVIEW_SYNTHESIS
- name: Hair diameter variability on trichoscopy
  category: Dermatologic
  description: Variation in shaft caliber is a useful trichoscopic clue to mixed terminal and miniaturized follicles. A 34-study review reports diameter variability in 94.07% of assessed AGA samples, but study thresholds, scalp areas, magnification and case/control selection differed. Some studies used greater than 20% variation in men or greater than 10% in women; no single threshold is established for every setting. No sufficiently specific HPO term was identified for this dermoscopic sign.
  evidence:
  - reference: PMID:38610726
    reference_title: 'Trichoscopy of Androgenetic Alopecia: A Systematic Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The most common features identified using trichoscopy included hair diameter variability (94.07% of patients), vellus hairs (66.45%) and the peripilar sign (43.27%).
    explanation: Pooled frequencies, 94.07% for diameter variability, in the VERY_FREQUENT band.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:38610726
    reference_title: 'Trichoscopy of Androgenetic Alopecia: A Systematic Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In the majority of male androgenetic alopecia cases, a patient's history and clinical evaluation may be sufficient to establish the diagnosis, while for women, they should be supplemented with trichoscopy.
    explanation: Why the sign matters more in the female pattern.
    quote_role: REVIEW_SYNTHESIS
- name: Peripilar sign on trichoscopy
  category: Dermatologic
  description: A brown perifollicular halo is associated with superficial perifollicular inflammation. A trichoscopy review summarizes its presence in 43.27% across 24 studies, with substantial variation in detection and heterogeneous controls. It is neither obligatory nor an individually definitive inflammatory or diagnostic test. No sufficiently specific HPO term was identified for this dermoscopic sign.
  evidence:
  - reference: PMID:38610726
    reference_title: 'Trichoscopy of Androgenetic Alopecia: A Systematic Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The most common features identified using trichoscopy included hair diameter variability (94.07% of patients), vellus hairs (66.45%) and the peripilar sign (43.27%).
    explanation: Pooled frequency of 43.27%, in the FREQUENT band.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:38610726
    reference_title: 'Trichoscopy of Androgenetic Alopecia: A Systematic Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The peripilar sign was more common in men (63.67%) than women (42.53%) (Table 1). The analysis showed that the calculated specificity was the highest among all the features (96.06%).
    explanation: The sex difference and the specificity that makes the sign diagnostically useful.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:38610726
    reference_title: 'Trichoscopy of Androgenetic Alopecia: A Systematic Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A conspicuous brown halo, also known as the peripilar sign, indicates perifollicular inflammation
    explanation: What the sign is and what it is taken to reflect, tying it to the microinflammation node.
    quote_role: REVIEW_SYNTHESIS
- name: Insulin resistance (associated)
  category: Metabolic
  description: Observational studies report higher insulin resistance and fasting insulin in some AGA populations. The 2026 meta-analysis pools cross-sectional or case-control associations, not longitudinal incident disease. Metabolic-syndrome associations in a Taiwanese survey and a selected Spanish early-onset case-control series vary by ascertainment. These findings do not prove that AGA causes insulin resistance or establish universal metabolic screening solely because of hair loss.
  phenotype_term:
    preferred_term: Insulin resistance (associated)
    term:
      id: HP:0000855
      label: Insulin resistance
  evidence:
  - reference: PMID:41606541
    reference_title: 'Risk factors for androgenetic alopecia: a systematic review and meta-analysis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A paternal family history of AGA (OR 2.22, 95% CI 1.59–3.10), insulin resistance (standardized mean difference [SMD] 0.40, 95% CI 0.27–0.53), and high fasting insulin levels (SMD 0.48, 95% CI 0.18–0.78) were also identified as factors that increased the risk of the presence of AGA.
    explanation: Pooled insulin resistance and fasting insulin differences.
    quote_role: PRIMARY_RESULT
  - reference: PMID:20426781
    reference_title: 'Association of androgenetic alopecia with metabolic syndrome in men: a community-based survey.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A statistically significant association was found between AGA and the presence of metabolic syndrome [odds ratio (OR) 1.67, 95% confidence interval (CI) 1.01-2.74] as well as between AGA and the number of fulfilled metabolic syndrome components (OR 1.21, 95% CI 1.03-1.42) after controlling for age, family history of AGA and smoking status.
    explanation: The community-based association with metabolic syndrome, adjusted for confounders.
    quote_role: PRIMARY_RESULT
  - reference: PMID:20619491
    reference_title: 'Androgenetic alopecia and cardiovascular risk factors in men and women: a comparative study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Metabolic syndrome was diagnosed in 60% of male patients with AGA (odds ratio [OR] = 10.5, 95% confidence interval [CI] 3.3-32.5), 48.6% of female patients with AGA (OR = 10.73, 95% CI 2.7-41.2), 12.5% of male control subjects, and 8.1% of female control subjects (P < .0001).
    explanation: The early-onset case-control finding in both sexes.
    quote_role: PRIMARY_RESULT
- name: Anxiety associated with hair loss
  category: Psychiatric
  description: Anxiety, body-image concerns and distress can accompany hair loss in some patients. However, among 892 examined men aged approximately 46 in the Oulu-area Northern Finland birth-cohort follow-up, AGA presence and severity were not significantly associated with measured anxiety or other psychosocial outcomes. This age- and sex-specific null finding does not exclude distress in individuals or other populations and does not prove that distress occurs only in care-seeking patients.
  phenotype_term:
    preferred_term: Anxiety
    term:
      id: HP:0000739
      label: Anxiety
  evidence:
  - reference: PMID:41606541
    reference_title: 'Risk factors for androgenetic alopecia: a systematic review and meta-analysis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The appearance of hair loss can impose a significant psychological burden on patients, leading to anxiety, low self-esteem, and severe impairment of personal life and social interaction [2].
    explanation: The introduction summarizes reported human psychosocial burden rather than a newly measured outcome in this meta-analysis.
    quote_role: BACKGROUND
  - reference: PMID:12196747
    reference_title: A randomized clinical trial of 5% topical minoxidil versus 2% topical minoxidil and placebo in the treatment of androgenetic alopecia in men.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: Additionally, data from a patient questionnaire on quality of life, global benefit, hair growth, and hair styling demonstrated that 5% topical minoxidil helped improve patients' psychosocial perceptions of hair loss.
    explanation: Treatment improved psychosocial perceptions in a trial population, which implies the perceptions were impaired; indirect because it is a treatment-response inference.
    quote_role: PRIMARY_RESULT
  - reference: PMID:39192534
    reference_title: 'Association between psychosocial distress, sexual disorders, self-esteem and quality of life with male androgenetic alopecia: a population-based study with men at age 46.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: There was no significant association between the presence of AGA or its severity with depression, anxiety, quality of life, self-esteem or sexual symptoms.
    explanation: The selected birth-cohort follow-up did not find an association at this age; this qualifies generalization rather than refuting distress in every patient.
    quote_role: PRIMARY_RESULT
histopathology:
- name: Reduced terminal-to-vellus hair ratio with fibrous streamers
  description: Horizontal sections permit terminal and vellus follicle counts and show miniaturization with increased fibrous streamers. In a series of 106 male-pattern cases and 22 controls, the affected-sample average terminal-to-vellus ratio was 1.7:1, and horizontal counts met the study diagnostic ratio in 67% of cases. These are study-specific observations, not universal diagnostic sensitivity. The diagnostic S1 guideline recommends considering both horizontal and vertical sections when biopsy is required, particularly to distinguish scarring or diffuse inflammatory disorders.
  evidence:
  - reference: PMID:8496421
    reference_title: Diagnostic and predictive value of horizontal sections of scalp biopsy specimens in male pattern androgenetic alopecia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The average horizontal section contained 22 terminal and 13 vellus hairs, a 1.7:1 ratio.
    explanation: The measured terminal-to-vellus ratio in affected men.
    quote_role: PRIMARY_RESULT
  - reference: PMID:8496421
    reference_title: Diagnostic and predictive value of horizontal sections of scalp biopsy specimens in male pattern androgenetic alopecia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Changes compatible with MPAA were found in most vertical and horizontal sections, but horizontal sections were required for follicular counts and showed terminal:vellus hair ratios diagnostic of MPAA in 67% of cases.
    explanation: Diagnostic yield of horizontal sectioning.
    quote_role: PRIMARY_RESULT
  - reference: PMID:15787815
    reference_title: Treatment of female pattern hair loss with oral antiandrogens.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 80 women aged between 12 and 79 years, with FPHL and biopsy-confirmed hair follicle miniaturization
    explanation: Biopsy-confirmed miniaturization was the entry criterion in the female series; the source's bracketed threshold (terminal to vellus ratio of 4 to 1 or below) cannot be quoted through the validator's bracket stripping and is described in the prose only.
    quote_role: PRIMARY_RESULT
diagnosis:
- name: Clinical pattern recognition with trichoscopy
  description: Diagnosis is usually clinical, based on gradual patterned nonscarring thinning and examination of the scalp. A negative family history does not exclude it. Trichoscopy can support the diagnosis and distinguish other alopecias, but heterogeneous research estimates do not establish a universal diagnostic cutoff. Follicular ostial loss, marked inflammation, rapid shedding or atypical distribution prompt assessment for an alternative or coexisting condition.
  evidence:
  - reference: PMID:38610726
    reference_title: 'Trichoscopy of Androgenetic Alopecia: A Systematic Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We concluded that hair diameter variability, vellus hairs and the peripilar sign represented valuable indicators for the diagnosis of androgenetic alopecia.
    explanation: The trichoscopic criteria from a systematic review of 34 studies.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:10882953
    reference_title: 'Current understanding of androgenetic alopecia. Part II: clinical aspects and treatment.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Only exceptionally laboratory tests or scalp biopsies are needed to confirm the diagnosis.
    explanation: The place of tests and biopsy in diagnosis.
    quote_role: REVIEW_SYNTHESIS
- name: Selective laboratory and endocrine evaluation
  description: Testing is guided by history and examination rather than a routine hormonal panel for every patient. Ferritin or thyroid evaluation may be appropriate with diffuse shedding or relevant symptoms. Women with hirsutism, acne, menstrual disturbance or other androgen-excess features may need endocrine assessment; unusually early onset warrants pediatric or endocrine evaluation.
  evidence:
  - reference: url:https://bhns.org.uk/ccs_files/web_data/Resources/Guidelines/european%20S1%20AGA%20guidelien.pdf
    reference_title: https://bhns.org.uk/ccs_files/web_data/Resources/Guidelines/european%20S1%20AGA%20guidelien.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Measurement of ferritin level or thyroid-stimulating hormone may be considered depending on the individual history, espe- cially in diffuse efﬂuvium.
    explanation: The S1 document provides expert diagnostic guidance rather than a validated screening algorithm.
- name: Scalp biopsy when the diagnosis is uncertain
  description: Biopsy is reserved for diagnostic uncertainty, particularly diffuse alopecia areata or suspected scarring alopecia. Horizontal sections quantify follicular populations; vertical sections provide complementary inflammatory and scarring information. Cohort-specific terminal-to-vellus ratios are interpreted with the clinical pattern rather than used as a universal stand-alone test.
  evidence:
  - reference: PMID:10882953
    reference_title: 'Current understanding of androgenetic alopecia. Part II: clinical aspects and treatment.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Only exceptionally laboratory tests or scalp biopsies are needed to confirm the diagnosis.
    explanation: The clinical review reserves laboratory investigations and biopsy for selected diagnostic circumstances.
  - reference: PMID:8496421
    reference_title: Diagnostic and predictive value of horizontal sections of scalp biopsy specimens in male pattern androgenetic alopecia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Changes compatible with MPAA were found in most vertical and horizontal sections, but horizontal sections were required for follicular counts and showed terminal:vellus hair ratios diagnostic of MPAA in 67% of cases.
    explanation: Horizontal follicle counts were useful in this selected biopsy series, without establishing population-level sensitivity.
genetic:
- name: Polygenic susceptibility with several hundred common loci
  relationship_type: SUSCEPTIBILITY
  notes: European male cohorts identify many common susceptibility signals. The 2017 eight-cohort early-onset meta-analysis included 10,846 cases and 11,672 controls and identified 63 loci; its approximately 39% value is binary case/control regression R-squared, not universal liability heritability. The 2018 UK Biobank analysis used self-reported severity in 205,327 European men aged 40–73. COJO selected 624 signals, with 622 retained after further X-chromosome LD pruning. The selected X variants explained 0.029 of phenotype-score variance, or 11.6% of the selected-SNP total 0.252, not 11.6% of all phenotypic variance. Cohorts and locus definitions overlap across reports and counts must not be added. Candidate-gene and pathway nominations do not establish causal mediation or clinical utility of polygenic testing. The 2017 52,874-man White British prediction study used an internal 40,000-person discovery subset and a 12,874-person target subset; its AUC 0.78 contrasts no-loss and severe-loss extremes, with the threshold selected in that same target set. It is not external prospective prediction, and predictive values depend on the selected comparison. The earlier eight-locus score OR
    5.78 comes from an independent extreme case-control comparison, not absolute lifetime risk.
  evidence:
  - reference: PMID:30573740
    reference_title: Dissection of genetic variation and evidence for pleiotropy in male pattern baldness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We detect 624 near-independent genome-wide loci, contributing SNP-heritability of 0.25 (SE = 0.01), of which 26 X-chromosome loci explain 11.6%.
    explanation: The abstract reports the initial 624 COJO signals; the full body removes two residual-LD X signals, and 11.6% uses selected-SNP variance as denominator.
    quote_role: PRIMARY_RESULT
  - reference: PMID:22693459
    reference_title: Six novel susceptibility Loci for early-onset androgenetic alopecia and their unexpected association with common diseases.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Individuals in the highest risk quartile of a genotype score had an approximately six-fold increased risk of early-onset AGA [odds ratio (OR) = 5.78, p = 1.4×10⁻⁸⁸].
    explanation: The top-versus-bottom quartile odds ratio is from an extreme case-control validation sample, not sixfold absolute population risk.
    quote_role: PRIMARY_RESULT
  - reference: PMID:22693459
    reference_title: Six novel susceptibility Loci for early-onset androgenetic alopecia and their unexpected association with common diseases.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Unexpectedly, we identified a risk allele at 17q21.31 that was recently associated with Parkinson's disease (PD) at a genome-wide significant level.
    explanation: The shared 17q21.31 haplotype behind the reported pleiotropy.
    quote_role: PRIMARY_RESULT
  - reference: PMID:28196072
    reference_title: Genetic prediction of male pattern baldness.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: By splitting the cohort into a discovery sample of 40,000 and target sample of 12,000, we developed a prediction algorithm based entirely on common genetic variants that discriminated (AUC = 0.78, sensitivity = 0.74, specificity = 0.69, PPV = 59%, NPV = 82%) those with no hair loss from those with severe hair loss.
    explanation: Internal holdout discrimination of severity extremes does not establish external prospective clinical utility; the abstract rounds the target sample size.
    quote_role: PRIMARY_RESULT
  - reference: PMID:27060448
    reference_title: Differential Expression between Human Dermal Papilla Cells from Balding and Non-Balding Scalps Reveals New Candidate Genes for Androgenetic Alopecia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Further, our data suggest TWIST1 (twist family basic helix-loop-helix transcription factor 1) and SSPN (sarcospan) to be the functionally relevant AGA genes at the 7p21.1 and 12p12.1 risk loci, respectively.
    explanation: Expression-based candidate gene assignment at two autosomal loci.
    quote_role: PRIMARY_RESULT
- name: AR
  gene_term:
    preferred_term: AR
    term:
      id: hgnc:644
      label: AR
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  notes: The AR/EDA2R interval is a strong common-variant susceptibility region. AR marker and repeat associations in early-onset male cohorts, including the study-specific etiological fraction of 0.46, do not establish a single causal repeat or pathogenic Mendelian allele. Regulatory effects on receptor abundance are plausible but not demonstrated for every risk haplotype. The X-linked signal does not make the entire polygenic disorder maternally inherited; autosomal susceptibility is substantial.
  evidence:
  - reference: PMID:15902657
    reference_title: Genetic variation in the human androgen receptor gene is the major determinant of common early-onset androgenetic alopecia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The investigation of a large number of genetic variants covering the AR locus suggests that a polyglycine-encoding GGN repeat in exon 1 is a plausible candidate for conferring the functional effect.
    explanation: The candidate functional variant at the locus.
    quote_role: PRIMARY_RESULT
  - reference: PMID:11231320
    reference_title: Polymorphism of the androgen receptor gene is associated with male pattern baldness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The androgen receptor gene StuI restriction site was found in all but one (98.1%) of the 54 young bald men (p = 0.0005) and in 92.3% of older balding men (p = 0.000004) but in only 76.6% of nonbald men.
    explanation: The original association at the AR locus.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:18385763
    reference_title: EDA2R is associated with androgenetic alopecia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We found that the non-synonymous SNP rs1385699 on EDA2R gave the best result (P=3.9e(-19)) whereas rs6152 on the AR gene is less significant (P=4.17e(-12)).
    explanation: The competing assignment of the X-linked signal to EDA2R, recorded here so that the AR entry does not overstate its case.
    quote_role: PRIMARY_RESULT
- name: EDA2R
  gene_term:
    preferred_term: EDA2R
    term:
      id: hgnc:17756
      label: EDA2R
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  notes: A Sardinian association study identified a nonsynonymous EDA2R variant whose statistical association persisted after conditioning on AR. This supports a susceptibility signal, not proof that EDA2R is the sole functional gene. Cultured dermal-papilla expression studies favor AR as a candidate in that preparation; expression differences and linkage disequilibrium do not settle allele-specific causality.
  evidence:
  - reference: PMID:18385763
    reference_title: EDA2R is associated with androgenetic alopecia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In particular, we found that rs1352015 located 8 kb from the EDA2R gene showed the best result (P=7.77e(-7)).
    explanation: The lead marker near EDA2R in the genome-wide X-chromosome scan.
    quote_role: PRIMARY_RESULT
  - reference: PMID:27060448
    reference_title: Differential Expression between Human Dermal Papilla Cells from Balding and Non-Balding Scalps Reveals New Candidate Genes for Androgenetic Alopecia.
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: We found evidence for AR but not EDA2R as the candidate gene at the AGA risk locus on chromosome X.
    explanation: Expression in balding papilla cells does not support EDA2R as the functional gene; recorded as REFUTE of the functional-gene claim, not of the association.
    quote_role: PRIMARY_RESULT
- name: 20p11.22 locus (PAX1/FOXA2 region)
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  notes: Independent 2008 studies associated the intergenic 20p11 region with male-pattern hair loss. PAX1 and FOXA2 are nearby candidates, not genes established by the association alone. Lack of detected statistical interaction with the AR locus does not prove an androgen-independent biochemical route.
  evidence:
  - reference: PMID:18849991
    reference_title: Male-pattern baldness susceptibility locus at 20p11.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We conducted a genome-wide association study for androgenic alopecia in 1,125 men and identified a newly associated locus at chromosome 20p11.22, confirmed in three independent cohorts (n = 1,650; OR = 1.60, P = 1.1 x 10(-14) for rs1160312).
    explanation: Discovery and replication of the locus.
    quote_role: PRIMARY_RESULT
  - reference: PMID:18849994
    reference_title: Susceptibility variants for male-pattern baldness on chromosome 20p11.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We then investigated the 30 best SNPs in an independent replication sample and found highly significant association for five SNPs on chromosome 20p11 (rs2180439 combined P = 2.7 x 10(-15)).
    explanation: The simultaneous independent discovery.
    quote_role: PRIMARY_RESULT
- name: WNT10A
  gene_term:
    preferred_term: WNT10A
    term:
      id: hgnc:13829
      label: WNT10A
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  notes: The intronic rs7349332 association and follicular expression make WNT10A a candidate at 2q35. These data do not establish that the risk allele causes the androgen-induced dermal-papilla Wnt changes measured in separate culture experiments. This common-variant susceptibility association is distinct from pathogenic WNT10A alleles causing ectodermal dysplasia.
  evidence:
  - reference: PMID:23358095
    reference_title: 'Androgenetic alopecia: identification of four genetic risk loci and evidence for the contribution of WNT signaling to its etiology.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Expression studies in human hair follicle tissue suggest that WNT10A has a functional role in AGA etiology.
    explanation: The expression evidence that the locus acts through WNT10A.
    quote_role: PRIMARY_RESULT
environmental:
- name: Tobacco smoking
  description: Smoking is associated with AGA presence and with greater cross-sectional severity in observational studies. In the 2026 review, the endpoint labeled progression compared moderate/severe with mild disease; no cohort studies established longitudinal worsening. Proposed oxidative or inflammatory mechanisms remain untested in the cited scalp evidence, and the association does not demonstrate that smoking cessation reverses AGA.
  exposure_term:
    preferred_term: exposure to tobacco smoking
    term:
      id: ECTO:6000029
      label: exposure to tobacco smoking
  influences_mechanisms:
  - target: Perifollicular Inflammation
    environmental_effect: EXACERBATES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Pro-oxidant effects of smoke are proposed to release pro-inflammatory cytokines and drive follicular microinflammation and fibrosis; the mechanism is proposed from general smoke biology rather than shown in scalp.
    evidence:
    - reference: PMID:12673073
      reference_title: 'Association between smoking and hair loss: another opportunity for health education against smoking?'
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: pro-oxidant effects of smoking leading to the release of pro-inflammatory cytokines resulting in follicular micro-inflammation and fibrosis
      explanation: The proposed route from smoke to the perifollicular inflammatory node; a review's mechanistic proposal, hence indirect.
      quote_role: REVIEW_SYNTHESIS
  evidence:
  - reference: PMID:41606541
    reference_title: 'Risk factors for androgenetic alopecia: a systematic review and meta-analysis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Family history (presence: odds ratio [OR] 2.72, 95% confidence interval [CI] 1.85–3.99; progression: OR 4.24, 95% CI 2.77–6.49) and smoking (presence: OR 1.46, 95% CI 1.06–2.01; progression: OR 1.60, 95% CI 1.29–1.99) were significantly associated with both presence and progression of AGA.'
    explanation: The reported progression odds ratio refers to cross-sectional severity categories; it is not a longitudinal progression rate.
  - reference: PMID:12673073
    reference_title: 'Association between smoking and hair loss: another opportunity for health education against smoking?'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Smoke-induced premature skin ageing has attracted the attention of the medical community, while only recently an observational study has indicated a significant relationship between smoking and baldness.
    explanation: The observational nature of the association as the review itself states it.
treatments:
- name: Topical minoxidil
  description: Topical minoxidil is an established treatment for adult male- and female-pattern hair loss. The S3 guideline recommends 2–5% solution or 5% foam twice daily in men, and 2% solution twice daily or 5% foam once daily in women. Assess response after about six months and continue effective therapy to maintain benefit. Temporary early shedding, irritation, contact allergy and unwanted hair growth should be discussed; the guideline advises pausing treatment during pregnancy and lactation. The follicular mechanism remains incompletely defined.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: minoxidil
      term:
        id: CHEBI:6942
        label: minoxidil
  target_mechanisms:
  - target: Shortened Anagen
    treatment_effect: INHIBITS
    description: Animal hair-cycle studies support earlier anagen entry and possible anagen prolongation. The exact human mechanism and the fraction of benefit attributable to this effect remain uncertain.
    evidence:
    - reference: PMID:14996087
      reference_title: 'Minoxidil: mechanisms of action on hair growth.'
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: REVIEW_SYNTHESIS
      snippet: In animal studies, topical minoxidil shortens telogen, causing premature entry of resting hair follicles into anagen, and it probably has a similar action in humans.
      explanation: The review explicitly distinguishes demonstrated animal cycle changes from proposed human similarity.
    - reference: PMID:14996087
      reference_title: 'Minoxidil: mechanisms of action on hair growth.'
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: REVIEW_SYNTHESIS
      snippet: Minoxidil may also cause prolongation of anagen and increases hair follicle size.
      explanation: Anagen prolongation is a proposed contributor in the mechanism review.
  evidence:
  - reference: PMID:12196747
    reference_title: A randomized clinical trial of 5% topical minoxidil versus 2% topical minoxidil and placebo in the treatment of androgenetic alopecia in men.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: In men with AGA, 5% topical minoxidil was clearly superior to 2% topical minoxidil and placebo in increasing hair regrowth, and the magnitude of its effect was marked (45% more hair regrowth than 2% topical minoxidil at week 48).
    explanation: The randomized male trial supports 5% topical efficacy; its relative gain does not apply to all preparations or populations.
  - reference: url:https://generolon.com/img/articles/Evidence-based-guideline-for-the-treatment-of-AGA-in-women-and-in-men.pdf
    reference_title: https://generolon.com/img/articles/Evidence-based-guideline-for-the-treatment-of-AGA-in-women-and-in-men.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: The response to treatment should be assessed at 6 months. If successful, treatment needs to be continued to maintain efﬁcacy.
    explanation: Guideline monitoring and continuation advice.
  - reference: url:https://generolon.com/img/articles/Evidence-based-guideline-for-the-treatment-of-AGA-in-women-and-in-men.pdf
    reference_title: https://generolon.com/img/articles/Evidence-based-guideline-for-the-treatment-of-AGA-in-women-and-in-men.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: It is recommended to pause topical minoxidil use during pregnancy and lactation, due to lack of data during this period.
    explanation: Pregnancy and lactation guidance is precautionary because of limited data.
- name: Low-dose oral minoxidil
  description: Oral minoxidil is used off-label for hair loss when topical treatment is unsuitable or insufficient. In a 24-week double-dummy trial of 90 selected men, 5 mg daily was not superior to 5% topical minoxidil twice daily for the primary absolute hair-density outcomes; this superiority trial does not establish equivalence. Hypertrichosis and headache were more frequent orally, and men with cardiac or renal disease were excluded. A 43-expert Delphi statement provides prescribing guidance, including cardiovascular and renal precautions and avoidance during pregnancy or breastfeeding; it is not proof of comparative safety. Regimen choice and monitoring require individual assessment.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: minoxidil
      term:
        id: CHEBI:6942
        label: minoxidil
  target_mechanisms:
  - target: Shortened Anagen
    treatment_effect: INHIBITS
    description: A possible hair-cycle effect of oral minoxidil is extrapolated from explicitly topical animal studies. This does not directly demonstrate anagen prolongation at the low oral doses used in patients.
    evidence:
    - reference: PMID:14996087
      reference_title: 'Minoxidil: mechanisms of action on hair growth.'
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: REVIEW_SYNTHESIS
      snippet: In animal studies, topical minoxidil shortens telogen, causing premature entry of resting hair follicles into anagen, and it probably has a similar action in humans.
      explanation: The review explicitly distinguishes demonstrated animal cycle changes from proposed human similarity.
      directness: INDIRECT
    - reference: PMID:14996087
      reference_title: 'Minoxidil: mechanisms of action on hair growth.'
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: REVIEW_SYNTHESIS
      snippet: Minoxidil may also cause prolongation of anagen and increases hair follicle size.
      explanation: Anagen prolongation is a proposed contributor in the mechanism review.
      directness: INDIRECT
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11007651/
    reference_title: 'Oral Minoxidil vs Topical Minoxidil for Male Androgenetic Alopecia: A Randomized Clinical Trial - PMC'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: In this double-blind, placebo-controlled randomized clinical trial including 90 men with androgenetic alopecia, daily oral minoxidil, 5 mg, was well tolerated and did not demonstrate superiority over topical minoxidil, 5%, in men with androgenetic alopecia after 24 weeks of treatment.
    explanation: The randomized comparison does not establish equivalence or long-term safety.
  - reference: url:https://www.newswise.com/pdf_docs/173213268899494_jamadermatology_akiska_2024_cs_240009_1732051708.84641%20%281%29.pdf
    reference_title: https://www.newswise.com/pdf_docs/173213268899494_jamadermatology_akiska_2024_cs_240009_1732051708.84641%20%281%29.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Contraindications for the use of LDOM Ongoing other drug therapy with significant oral minoxidil interaction 38 (86.4) 1 History of pericardial effusion/tamponade 36 (81.8) 1 History of pericarditis 32 (72.7) 1 Congestive heart failure 34 (79.1) 2 History of pulmonary hypertension associated with mitral stenosis 33 (76.7) 2 Pheochromocytoma 32 (74.4) 3 Patients who are pregnant or breastfeeding 42 (95.5) 1
    explanation: The consensus table defines contraindications; its counts are expert votes rather than adverse-event rates.
  - reference: url:https://www.newswise.com/pdf_docs/173213268899494_jamadermatology_akiska_2024_cs_240009_1732051708.84641%20%281%29.pdf
    reference_title: https://www.newswise.com/pdf_docs/173213268899494_jamadermatology_akiska_2024_cs_240009_1732051708.84641%20%281%29.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Precautions for the use of LDOM History of tachycardia or other arrhythmia 36 (81.8) 1 Hypotension (blood pressure <90/60 mm Hg) 34 (77.3) 1 Kidney function impairment 38 (88.4) 2 Patients undergoing dialysis 38 (88.4) 2
    explanation: The listed cardiovascular and renal precautions inform individualized prescribing.
- name: Finasteride
  description: Oral finasteride 1 mg daily inhibits type 2 5-alpha-reductase and is an established option for adult men with mild-to-moderate male-pattern hair loss. In two trials with 1,553 men during year one, target-area differences versus placebo were 107 hairs at one year and 138 at two years; these are between-group differences, not simple gains from baseline. Response may require 6–12 months and ongoing therapy. Counsel about sexual adverse effects and reduced PSA values. The 2025 EMA review confirms suicidal ideation as an adverse effect of finasteride tablets of unknown frequency and advises men taking 1 mg for hair loss to stop and seek advice if mood changes occur. Pregnancy exposure is contraindicated. The negative 1-mg postmenopausal-women trial does not exclude every female dose or subgroup.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: finasteride
      term:
        id: CHEBI:5062
        label: finasteride
  target_mechanisms:
  - target: Local Dihydrotestosterone Production
    treatment_effect: INHIBITS
    description: Blocks type 2 5-alpha-reductase, the enzyme of this node, lowering scalp dihydrotestosterone.
    evidence:
    - reference: PMID:9777765
      reference_title: Finasteride in the treatment of men with androgenetic alopecia. Finasteride Male Pattern Hair Loss Study Group.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Finasteride, an inhibitor of type II 5alpha-reductase, decreases serum and scalp DHT by inhibiting conversion of testosterone to DHT.
      explanation: The drug acts on exactly the conversion this node describes.
  - target: Follicular Miniaturization
    treatment_effect: INHIBITS
    description: Reduced androgen drive is associated with clinical regrowth and a histologic trend toward less miniaturization; this does not establish restoration of every proposed cellular mechanism.
    evidence:
    - reference: PMID:12573818
      reference_title: Androgens and alopecia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Controlled clinical trials with finasteride demonstrated improvements in scalp hair growth in treated men associated with reductions in scalp DHT content, and a trend towards reversal of scalp hair miniaturization was evident by histopathologic evaluation of scalp biopsies.
      explanation: The review reports a histological trend toward reversal of miniaturization, not uniform restoration of every follicle.
  evidence:
  - reference: PMID:9777765
    reference_title: Finasteride in the treatment of men with androgenetic alopecia. Finasteride Male Pattern Hair Loss Study Group.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In men with male pattern hair loss, finasteride 1 mg/d slowed the progression of hair loss and increased hair growth in clinical trials over 2 years.
    explanation: The pivotal trial conclusion.
  - reference: PMID:9777765
    reference_title: Finasteride in the treatment of men with androgenetic alopecia. Finasteride Male Pattern Hair Loss Study Group.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Clinically significant increases in hair count (baseline = 876 hairs), measured in a 1-inch diameter circular area (5.1 cm2) of balding vertex scalp, were observed with finasteride treatment (107 and 138 hairs vs placebo at 1 and 2 years, respectively; P < .001).
    explanation: The magnitude of the effect on hair counts.
  - reference: PMID:12573818
    reference_title: Androgens and alopecia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In contrast to its beneficial effects in men, finasteride did not improve hair growth in postmenopausal women with FPHL.
    explanation: The 1-mg postmenopausal trial limits generalization of efficacy to that population; it does not refute efficacy in men.
  - reference: url:https://www.ema.europa.eu/en/documents/referral/finasteride-dutasteride-containing-medicinal-products-article-31-referral-measures-minimise-risk-suicidal-thoughts-finasteride-dutasteride-medicines_en.pdf
    reference_title: https://www.ema.europa.eu/en/documents/referral/finasteride-dutasteride-containing-medicinal-products-article-31-referral-measures-minimise-risk-suicidal-thoughts-finasteride-dutasteride-medicines_en.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: suicidal ideation (suicidal thoughts) as a side effect of finasteride 1 and 5 mg tablets.
    explanation: EMA safety review identifies a reported adverse effect whose frequency cannot be estimated.
  - reference: url:https://www.ema.europa.eu/en/documents/referral/finasteride-dutasteride-containing-medicinal-products-article-31-referral-measures-minimise-risk-suicidal-thoughts-finasteride-dutasteride-medicines_en.pdf
    reference_title: https://www.ema.europa.eu/en/documents/referral/finasteride-dutasteride-containing-medicinal-products-article-31-referral-measures-minimise-risk-suicidal-thoughts-finasteride-dutasteride-medicines_en.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: The frequency of the side effect is unknown, meaning that it is not possible to estimate it from available data.
    explanation: The regulatory review cannot estimate the frequency of suicidal ideation.
  - reference: url:https://www.ema.europa.eu/en/documents/referral/finasteride-dutasteride-containing-medicinal-products-article-31-referral-measures-minimise-risk-suicidal-thoughts-finasteride-dutasteride-medicines_en.pdf
    reference_title: https://www.ema.europa.eu/en/documents/referral/finasteride-dutasteride-containing-medicinal-products-article-31-referral-measures-minimise-risk-suicidal-thoughts-finasteride-dutasteride-medicines_en.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Patients who experience mood changes should seek medical advice and, if taking finasteride 1 mg, should also stop treatment.
    explanation: EMA advises medical review and stopping 1-mg finasteride for hair loss when mood changes occur.
- name: Dutasteride
  description: Dutasteride inhibits type 1 and type 2 5-alpha-reductase. A 416-man, 24-week dose-ranging trial showed increasing hair counts with dose; superiority over finasteride involved dutasteride 2.5 mg versus finasteride 5 mg, not a 0.5-versus-1-mg comparison. The S3 guideline considers 0.5 mg daily as an off-label second-line option after ineffective finasteride treatment. Sexual and reproductive precautions require counseling. The 2025 EMA review did not establish a causal link between dutasteride and suicidal ideation; a warning was added as a class precaution, which should not be described as the same proven drug-specific finding as for finasteride.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: dutasteride
      term:
        id: CHEBI:521033
        label: dutasteride
  target_mechanisms:
  - target: Local Dihydrotestosterone Production
    treatment_effect: INHIBITS
    description: Dual 5-alpha-reductase inhibition reduces measured scalp and serum DHT in the dose-ranging trial.
    evidence:
    - reference: PMID:17110217
      reference_title: 'The importance of dual 5alpha-reductase inhibition in the treatment of male pattern hair loss: results of a randomized placebo-controlled study of dutasteride versus finasteride.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Scalp and serum dihydrotestosterone levels decreased, and testosterone levels increased, in a dose-dependent fashion with dutasteride.
      explanation: The pharmacodynamic effect on the node's product.
  evidence:
  - reference: PMID:17110217
    reference_title: 'The importance of dual 5alpha-reductase inhibition in the treatment of male pattern hair loss: results of a randomized placebo-controlled study of dutasteride versus finasteride.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Dutasteride increased target area hair count versus placebo in a dose-dependent fashion and dutasteride 2.5 mg was superior to finasteride at 12 and 24 weeks.
    explanation: The randomized comparison against placebo and finasteride.
  - reference: url:https://generolon.com/img/articles/Evidence-based-guideline-for-the-treatment-of-AGA-in-women-and-in-men.pdf
    reference_title: https://generolon.com/img/articles/Evidence-based-guideline-for-the-treatment-of-AGA-in-women-and-in-men.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: In case of ineffective treatment with 1 mg ﬁnasteride over 12 months, the off-label use of dutasteride 0.5 mg/day can be considered.
    explanation: Guideline second-line consideration, not a universal escalation requirement.
  - reference: url:https://www.ema.europa.eu/en/documents/referral/finasteride-dutasteride-containing-medicinal-products-article-31-referral-measures-minimise-risk-suicidal-thoughts-finasteride-dutasteride-medicines_en.pdf
    reference_title: https://www.ema.europa.eu/en/documents/referral/finasteride-dutasteride-containing-medicinal-products-article-31-referral-measures-minimise-risk-suicidal-thoughts-finasteride-dutasteride-medicines_en.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Although it was not possible to establish a link between suicidal ideation and dutasteride based on the reviewed data, dutasteride works in the same way as finasteride and therefore information about the EMA/142716/2025 Page 2/4 mood changes seen with finasteride will also be added to dutasteride’s product information as a precaution.
    explanation: The dutasteride warning is precautionary rather than confirmation of a causal association.
- name: Spironolactone for female-pattern hair loss
  description: Spironolactone is an off-label option in selected women, with pregnancy avoidance and assessment of renal function, potassium and blood-pressure risks. The older uncontrolled series combining spironolactone and cyproterone groups reported regrowth in 44% and stability in 44%, without proving efficacy against natural history. A 2025 pilot randomized 48 healthy premenopausal women to spironolactone 100 mg or placebo, both with topical 3% minoxidil for 24 weeks. The primary total and terminal hair-count differences were not statistically significant; a dichotomized photographic improvement endpoint favored spironolactone. Menstrual irregularity occurred in 9 of 24 assigned spironolactone and led to two withdrawals. These small adjunct data do not establish benefit in all female-pattern populations.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: spironolactone
      term:
        id: CHEBI:9241
        label: spironolactone
  target_mechanisms:
  - target: Dihydrotestosterone-Androgen Receptor Signaling
    treatment_effect: INHIBITS
    description: Androgen-receptor antagonism is the pharmacologic rationale for selected use. Clinical hair-count response does not demonstrate dermal-papilla receptor mediation in every woman.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK430924/
      reference_title: Androgenetic Alopecia - StatPearls - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: REVIEW_SYNTHESIS
      snippet: androgen receptor, physiologically behaving like a direct antagonist.
      explanation: The chapter summarizes receptor antagonism; this is separate from clinical response evidence.
  evidence:
  - reference: PMID:15787815
    reference_title: Treatment of female pattern hair loss with oral antiandrogens.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Thirty-five (44%) women had hair regrowth, 35 (44%) had no clear change in hair density before and after treatment, and 10 (12%) experienced continuing hair loss during the treatment period.
    explanation: Uncontrolled responses cannot distinguish treatment effect from natural history.
  - &id011
    reference: PMID:40978669
    reference_title: 'Efficacy and safety of oral spironolactone for female pattern hair loss in premenopausal women: a randomized, double-blind, placebo-controlled, parallel-group pilot study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: However, only the P-value of terminal hair counts approached the cutoff of statistical significance (P = .063).
    explanation: The primary hair-count comparison was imprecise and not statistically significant.
- name: Low-level laser therapy (photobiomodulation)
  description: Specific low-level laser devices can increase terminal hair density. Four sham-controlled trials randomized 269 adults, with 225 having at least one post-randomization efficacy assessment. At 26 weeks, the pooled adjusted between-group difference was 15.27 hairs/cm²; reported 18–26-hair gains were within active-treatment groups, not the difference versus sham. Participants were predominantly Caucasian, and long-term durability and the optimal device regimen remain uncertain. The S3 guideline suggests LLLT as ancillary care using devices with trial-supported energy settings.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: low-level laser (photobiomodulation) therapy
    term:
      id: NCIT:C21063
      label: Photobiomodulation Therapy
  target_mechanisms:
  - target: Patterned non-scarring scalp hair loss
    treatment_effect: INHIBITS
    description: Reported hair-density improvement addresses visible scalp thinning. The cited endpoint does not establish reversal of miniaturized follicle histology or a specific cellular mechanism.
    evidence:
    - reference: PMID:24474647
      reference_title: 'Efficacy and safety of a low-level laser device in the treatment of male and female pattern hair loss: a multicenter, randomized, sham device-controlled, double-blind study.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: The overall results showed the least squares mean difference of change in terminal hair density of 15.27 (standard error 1.781) at 26 weeks from baseline between lasercomb- and sham treated subjects, which was highly statistically significant (p < 0.0001).
      explanation: The pooled adjusted difference is the between-group treatment estimate.
  evidence:
  - reference: PMID:24474647
    reference_title: 'Efficacy and safety of a low-level laser device in the treatment of male and female pattern hair loss: a multicenter, randomized, sham device-controlled, double-blind study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Randomized, sham device-controlled, double-blind clinical trials were conducted at multiple institutional and private practices.
    explanation: The design of the trials supporting the device.
  - reference: PMID:24474647
    reference_title: 'Efficacy and safety of a low-level laser device in the treatment of male and female pattern hair loss: a multicenter, randomized, sham device-controlled, double-blind study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: The overall results showed the least squares mean difference of change in terminal hair density of 15.27 (standard error 1.781) at 26 weeks from baseline between lasercomb- and sham treated subjects, which was highly statistically significant (p < 0.0001).
    explanation: The pooled adjusted difference is the between-group treatment estimate.
- name: Platelet-rich plasma injection
  description: Autologous platelet-rich plasma scalp injection has shown improved hair-density outcomes in pooled trials, but preparation, activation, injection schedule and outcomes differ. The cited meta-analysis reports a standardized mean difference of 0.51 versus placebo; this is not an absolute hair count. The 2018 S3 guideline could not recommend for or against PRP because of limited evidence and absent standardization, while a 2025 Canadian Delphi panel recommends it. These are different evidence dates and consensus processes. Patient growth-factor mediation and an optimal maintenance schedule remain unresolved.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: autologous platelet-rich plasma scalp injection
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  target_mechanisms:
  - target: Patterned non-scarring scalp hair loss
    treatment_effect: INHIBITS
    description: Reported hair-density improvement addresses visible scalp thinning. The cited endpoint does not establish reversal of miniaturized follicle histology or a specific cellular mechanism.
    evidence:
    - reference: PMID:30882509
      reference_title: Platelet-Rich Plasma as a Treatment for Androgenetic Alopecia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'The overall SMD in hair density was 0.58 (95% confidence interval [CI]: 0.35-0.80) and 0.51 (95% CI: 0.23-0.80, p < .0004) in favor of PRP treatment when compared with baseline and placebo treatment, respectively.'
      explanation: The pooled effect size against baseline and placebo.
  evidence:
  - reference: PMID:30882509
    reference_title: Platelet-Rich Plasma as a Treatment for Androgenetic Alopecia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'The overall SMD in hair density was 0.58 (95% confidence interval [CI]: 0.35-0.80) and 0.51 (95% CI: 0.23-0.80, p < .0004) in favor of PRP treatment when compared with baseline and placebo treatment, respectively.'
    explanation: The pooled effect size against baseline and placebo.
  - reference: PMID:40986632
    reference_title: 'A Canadian Consensus on Androgenetic Alopecia: Approach and Management.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Seven interventions are recommended, including oral dutasteride; oral finasteride; topical finasteride; topical minoxidil; platelet-rich plasma; microneedling; and oral minoxidil.
    explanation: The 2025 Canadian panel recommendation is consensus, not a new trial.
- name: Hair transplantation (follicular unit transplantation or extraction)
  description: Follicular-unit transplantation or extraction redistributes donor hair to affected scalp and can improve coverage in appropriately selected patients. Adequate donor supply, realistic expectations and stable or medically controlled disease are important. Extraction avoids a linear donor incision but is not scar-free, and transplanted coverage does not prevent progression of native susceptible hair. The S3 guideline considers surgery in suitable men and women; combination medical therapy may help preserve non-transplanted hair.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: hair transplantation
    term:
      id: NCIT:C219973
      label: Hair-Bearing Skin Graft Transplantation
  target_mechanisms:
  - target: Follicular Miniaturization
    treatment_effect: BYPASSES
    description: Transplantation adds donor follicles to thinning areas rather than reversing miniaturization in the pre-existing affected follicles.
    evidence:
    - reference: PMID:12174065
      reference_title: 'Follicular unit extraction: minimally invasive surgery for hair transplantation.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: FUE is a minimally invasive approach to hair transplantation that obviates the need for a linear donor incision.
      explanation: The intervention moves follicular units and changes coverage, not the molecular state of resident follicles.
  evidence:
  - reference: PMID:16039422
    reference_title: 'Follicular unit transplantation: 2005.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The recognition that the follicular unit is a discrete, anatomic and physiologic entity, and that preserving it through stereomicroscopic dissection is the best way to ensure the naturalness of the restoration, has brought hair transplantation into the twenty-first century.
    explanation: The follicular unit principle behind modern transplantation.
  - reference: PMID:16039422
    reference_title: 'Follicular unit transplantation: 2005.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The essence of providing the best care for patients rests on proper patient selection, establishing realistic expectations, and using nonsurgical management for young persons who are just starting to thin.
    explanation: Patient selection and the place of medical therapy first.
  - reference: PMID:12174065
    reference_title: 'Follicular unit extraction: minimally invasive surgery for hair transplantation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: FUE is a minimally invasive approach to hair transplantation that obviates the need for a linear donor incision.
    explanation: The extraction alternative to strip harvest.
- name: Microneedling adjunct to topical minoxidil
  description: Scalp microneedling is used as an adjunct to topical therapy. A 12-week pilot randomized 100 men to weekly 1.5-mm microneedling plus 5% minoxidil or minoxidil alone; 94 were analyzed, with all six early dropouts in the minoxidil-only arm. Hair-count gains were 91.4 versus 22.2 per cm², but patient-reported improvement was unblinded and long-term durability was not established. The study did not measure patient Wnt activation or stem-cell conversion. Later consensus recommendations exist, so it is not accurately described as a single unreplicated intervention.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: scalp microneedling (dermaroller) with topical minoxidil
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  target_mechanisms:
  - target: Patterned non-scarring scalp hair loss
    treatment_effect: INHIBITS
    description: Reported hair-density improvement addresses visible scalp thinning. The cited endpoint does not establish reversal of miniaturized follicle histology or a specific cellular mechanism.
    evidence:
    - reference: PMID:23960389
      reference_title: 'A randomized evaluator blinded study of effect of microneedling in androgenetic alopecia: a pilot study.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: The mean change in hair count at week 12 was significantly greater for the Microneedling group compared to the Minoxidil group (91.4 vs 22.2 respectively).
      explanation: The pilot measures short-term hair-count change, not Wnt activation or histological reversal.
  evidence:
  - reference: PMID:23960389
    reference_title: 'A randomized evaluator blinded study of effect of microneedling in androgenetic alopecia: a pilot study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: After randomization one group was offered weekly microneedling treatment with twice daily 5% minoxidil lotion (Microneedling group); other group was given only 5% minoxidil lotion.
    explanation: The combination-versus-minoxidil-alone design.
  - reference: PMID:23960389
    reference_title: 'A randomized evaluator blinded study of effect of microneedling in androgenetic alopecia: a pilot study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The mean change in hair count at week 12 was significantly greater for the Microneedling group compared to the Minoxidil group (91.4 vs 22.2 respectively).
    explanation: The primary hair-count result favouring the combination.
  - reference: PMID:23960389
    reference_title: 'A randomized evaluator blinded study of effect of microneedling in androgenetic alopecia: a pilot study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In the Microneedling group, 41 (82%) patients reported more than 50% improvement versus only 2 (4.5%) patients in the Minoxidil group. Unsatisfied patients to conventional therapy for AGA got good response with Microneedling treatment.
    explanation: Patient-assessed response and the response in prior non-responders.
  - reference: PMID:40986632
    reference_title: 'A Canadian Consensus on Androgenetic Alopecia: Approach and Management.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Seven interventions are recommended, including oral dutasteride; oral finasteride; topical finasteride; topical minoxidil; platelet-rich plasma; microneedling; and oral minoxidil.
    explanation: The current Canadian panel includes microneedling among recommended interventions, without resolving its patient-level mechanism.
- name: Topical finasteride
  description: A formulation-specific 24-week trial randomized 458 men aged 18–40 with mild-to-moderate vertex hair loss to topical finasteride 0.25% spray, placebo or oral finasteride 1 mg. Topical treatment improved target-area hair count versus placebo; the protocol-defined primary analysis included only 250 men with valid baseline and on-treatment photographs, although post hoc sensitivity analyses supported the direction of benefit. Numerical similarity to oral treatment does not establish efficacy equivalence. Plasma exposure was substantially lower with topical treatment, but serum DHT still fell and systemic adverse effects remain possible. Low sexual-event counts and short follow-up do not establish superior long-term safety. Evidence for this specific spray should not be generalized to every compounded formulation or to women.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: finasteride
      term:
        id: CHEBI:5062
        label: finasteride
  target_mechanisms:
  - target: Patterned non-scarring scalp hair loss
    treatment_effect: INHIBITS
    description: The trial measures improvement in vertex hair count; it does not demonstrate reversal of each proposed cellular mechanism or increased hair width.
    evidence:
    - reference: PMID:34634163
      reference_title: 'Efficacy and safety of topical finasteride spray solution for male androgenetic alopecia: a phase III, randomized, controlled clinical trial.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: At week 24, the adjusted mean change from baseline in TAHC was significantly greater with topical finasteride than with placebo (20.2 vs. 6.7 hairs; P < 0.001), and was numerically similar to that with oral finasteride (21.1 hairs; Fig. 3).
      explanation: The primary hair-count comparison supports superiority to placebo; the numerical oral comparison was not an efficacy-equivalence test.
  evidence:
  - reference: PMID:34634163
    reference_title: 'Efficacy and safety of topical finasteride spray solution for male androgenetic alopecia: a phase III, randomized, controlled clinical trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: At week 24, the adjusted mean change from baseline in TAHC was significantly greater with topical finasteride than with placebo (20.2 vs. 6.7 hairs; P < 0.001), and was numerically similar to that with oral finasteride (21.1 hairs; Fig. 3).
    explanation: The primary hair-count comparison supports superiority to placebo; the numerical oral comparison was not an efficacy-equivalence test.
  - reference: PMID:34634163
    reference_title: 'Efficacy and safety of topical finasteride spray solution for male androgenetic alopecia: a phase III, randomized, controlled clinical trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Overall, 250 patients (54.6%) had evaluable hair count measurements from the macrophotographs both at baseline and on treatment and formed the ITT population.
    explanation: Only 250 of 458 randomized participants entered the protocol-defined primary efficacy analysis because valid baseline and on-treatment macrophotographs were required.
  - reference: PMID:34634163
    reference_title: 'Efficacy and safety of topical finasteride spray solution for male androgenetic alopecia: a phase III, randomized, controlled clinical trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Mean serum DHT concentrations at week 24 were 34.6% lower than at baseline in the topical finasteride group (25.75 vs. 39.32 ng/dL, respectively), and were 55.6% lower than at baseline in the oral finasteride group (15.75 vs. 35.50 ng/dL, respectively).
    explanation: Serum DHT remained suppressed with topical treatment, despite lower systemic finasteride exposure. The full results report 34.6%, rounded differently from the abstract.
  - reference: PMID:34634163
    reference_title: 'Efficacy and safety of topical finasteride spray solution for male androgenetic alopecia: a phase III, randomized, controlled clinical trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Treatment‐related sexual adverse events (sexual dysfunction, erectile dysfunction, libido decreased, loss of libido) were reported in 2.8% vs. 3.3% vs. 4.8% of patients treated with topical finasteride, placebo, or oral finasteride.
    explanation: Sexual adverse-event counts were low over 24 weeks; these descriptive rates do not establish superior long-term safety.
animal_models:
- name: Stump-tailed macaque spontaneous frontal balding
  species: Macaca arctoides
  genotype: Wild type; naturally occurring frontal balding
  publication: PMID:7962310
  description: Adult stump-tailed macaques of both sexes can develop frontal follicular regression. In a six-month study, 11 animals received oral finasteride 1 mg/kg/day and 10 received vehicle. Treated animals had greater frontal hair-weight gain than controls and increased follicle length relative to their own baseline. These observations support androgen-sensitive follicular growth in a primate model, not equivalence to the human genetic architecture, pattern or clinical dosing.
  evidence:
  - &id006
    reference: PMID:7962310
    reference_title: The effects of finasteride (Proscar) on hair growth, hair cycle stage, and serum testosterone and dihydrotestosterone in adult male and female stumptail macaques (Macaca arctoides).
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: Both males and females showed statistically significant increases in mean hair weight over the treatment period compared to controls (P = 0.034).
    explanation: Hair weight increased relative to vehicle in the 21-animal study, distinct from the within-treated baseline follicle-length comparison.
  - &id007
    reference: PMID:7962310
    reference_title: The effects of finasteride (Proscar) on hair growth, hair cycle stage, and serum testosterone and dihydrotestosterone in adult male and female stumptail macaques (Macaca arctoides).
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: In addition, there was a statistically significant increase in mean follicle length (measured histologically in scalp biopsies) compared to baseline in the finasteride-treated animals (P = 0.028).
    explanation: The follicle-length significance is relative to treated-animal baseline, not stated as a between-group effect in the abstract.
  modeled_mechanisms:
  - target: Follicular Miniaturization
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: The model displays age-related follicular regression and growth responses under DHT-lowering treatment.
    limitations: Small mixed-sex primate study; hair weight and follicle length do not measure human dermal-papilla cell rescue or every miniaturization pathway.
    evidence:
    - *id006
    - *id007
    readouts:
    - name: Frontal hair weight during finasteride treatment
      target: Follicular Miniaturization
      direction: INCREASED
      interpretation: Treatment increased hair output compared with vehicle.
      evidence:
      - *id006
    - name: Follicle length during finasteride treatment
      target: Follicular Miniaturization
      direction: INCREASED
      interpretation: Length increased from baseline within treated animals.
      evidence:
      - *id007
- name: K14-Ptgs2 mouse with altered skin prostanoids
  species: Mouse
  genotype: K14-Ptgs2 transgenic
  publication: PMID:22440736
  description: Skin-targeted Ptgs2 overexpression increased PGD2 and 15-dPGJ2, but also PGE2, and was associated with alopecia, miniaturization and sebaceous enlargement. This is an altered-prostanoid model, not proof that PGD2 alone causes all findings. Gpr44 epistasis was not tested in this transgenic background.
  evidence:
  - &id008
    reference: PMID:22440736
    reference_title: Prostaglandin D2 inhibits hair growth and is elevated in bald scalp of men with androgenetic alopecia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: Furthermore, we find that a transgenic mouse, K14-Ptgs2, which targets prostaglandin-endoperoxide synthase 2 expression to the skin, demonstrates elevated levels of PGD(2) in the skin and develops alopecia, follicular miniaturization, and sebaceous gland hyperplasia, which are all hallmarks of human AGA.
    explanation: The K14-Ptgs2 model changes upstream prostanoid production and develops hair phenotypes; it is not a selective PGD2 manipulation.
  - reference: PMID:22440736
    reference_title: Prostaglandin D2 inhibits hair growth and is elevated in bald scalp of men with androgenetic alopecia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: PGE2 was elevated in the K14-Ptgs2 mice compared to age-matched wild-type controls
    explanation: PGE2 elevation demonstrates that the transgenic perturbation is not selective for PGD2.
  modeled_mechanisms:
  - target: Prostaglandin D2 Elevation in Bald Scalp
    relationship: PERTURBS
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: Upstream cyclooxygenase overexpression increases skin PGD2.
    limitations: Multiple prostanoids change; the manipulation does not identify the cause of human scalp PGD2 elevation.
    evidence:
    - *id008
  - target: Follicular Miniaturization
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: Miniaturization and alopecia accompany altered skin prostanoid production.
    limitations: No selective PGD2 sufficiency or human androgen-pattern mechanism is established.
    evidence:
    - *id008
- name: Topical PGD2 challenge in prostaglandin-receptor knockout mice
  species: Mouse
  genotype: Gpr44-null, Ptgdr-null, Ptgds-null and comparator mice
  publication: PMID:22440736
  description: Topical PGD2 inhibited mouse hair lengthening in susceptible comparator genotypes, while Gpr44-null mice were resistant. Ptgdr-null and Ptgds-null mice remained sensitive. This tests receptor dependence of an induced growth-inhibition endpoint. Topical treatment did not induce premature catagen and does not establish reversal of established human AGA by GPR44 blockade.
  evidence:
  - *id009
  - reference: PMID:22440736
    reference_title: Prostaglandin D2 inhibits hair growth and is elevated in bald scalp of men with androgenetic alopecia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: Although we did not elicit premature catagen in mice treated topically with PGD2, we observed a negative effect on hair growth
    explanation: The investigators explicitly did not elicit early catagen with topical PGD2.
  modeled_mechanisms:
  - target: PGD2-Associated Hair Growth Inhibition
    relationship: PERTURBS
    fidelity: MODERATE
    model_scale: CELLULAR
    description: The genotype comparison tests Gpr44 dependence of the topical response.
    limitations: Mouse induced endpoint; no human receptor knockout, clinical regrowth or obligatory catagen sequence.
    evidence:
    - *id009
- name: Recombinant IL6 injection during mouse anagen
  species: Mouse
  publication: PMID:21881585
  description: Recombinant human IL6 injected into the mouse hypodermis during anagen caused early catagen. This is a cytokine perturbation of the hair cycle, distinct from the human follicle organ-culture proliferation experiment and from chronic androgenetic alopecia.
  evidence:
  - &id010
    reference: PMID:21881585
    reference_title: Dihydrotestosterone-inducible IL-6 inhibits elongation of human hair shafts by suppressing matrix cell proliferation and promotes regression of hair follicles in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: Moreover, rhIL-6 injection into the hypodermis of mice during anagen caused premature onset of catagen.
    explanation: The in-vivo cycle intervention is recombinant IL6 injection in mice.
  modeled_mechanisms:
  - target: Shortened Anagen
    relationship: PERTURBS
    fidelity: MODERATE
    model_scale: TISSUE
    description: The induced early catagen endpoint shortens the active-growth interval.
    limitations: Does not demonstrate that endogenous IL6 is necessary for human AGA or model its regional susceptibility.
    evidence:
    - *id010
    readouts:
    - name: Duration of anagen after IL6 injection
      target: Shortened Anagen
      direction: DECREASED
      interpretation: Early catagen follows experimental cytokine exposure.
      evidence:
      - *id010
prevalence:
- population: Men aged 18-49, US community sample
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 42000.0
  notes: The US community sample reported Norwood type III or greater in 42% of examined men aged 18–49. Separate age-stratum rates were 16% at 18–29 and 53% at 40–49; these are not confidence-interval bounds.
  evidence:
  - reference: PMID:9865198
    reference_title: Prevalence of male pattern hair loss in 18-49 year old men.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The proportion of men with moderate to extensive hair loss increased with increasing age, ranging from 16% for men 18-29 years of age to 53% of men 40-49.
    explanation: The age-stratified prevalence in a community sample.
    quote_role: PRIMARY_RESULT
  - reference: PMID:9865198
    reference_title: Prevalence of male pattern hair loss in 18-49 year old men.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The proportion of men with moderate to extensive hair loss (type III or greater) was 42%.
    explanation: The overall figure recorded as the rate.
    quote_role: PRIMARY_RESULT
- population: Men aged 46, Northern Finland Birth Cohort 1966
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 68500.0
  notes: AGA was identified in 611 of 892 examined men (68.5%) aged 45.3–47.6 in the Oulu-area follow-up. Of 3,181 invited cohort members of both sexes, 1,932 attended; this is not an examination of the entire birth cohort. Mild/moderate/severe percentages 39.0/33.2/27.8 use the 611 affected men as denominator.
  evidence:
  - reference: PMID:39192534
    reference_title: 'Association between psychosocial distress, sexual disorders, self-esteem and quality of life with male androgenetic alopecia: a population-based study with men at age 46.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: AGA was found in 68.5% of subjects, 27.8% of the cases were severe, 33.2% moderate and 39.0% mild.
    explanation: Dermatologist-ascertained prevalence among the examined Oulu-area male follow-up participants; subtype percentages use cases as denominator.
    quote_role: PRIMARY_RESULT
- population: Older Caucasian men, review estimate
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 80000.0
  notes: The S3 guideline summarizes signs of AGA in up to 80% of Caucasian men by age 70 or later. This is an age-specific review estimate, not a prospectively measured lifetime incidence or a rate applicable across ancestries.
  evidence:
  - reference: url:https://generolon.com/img/articles/Evidence-based-guideline-for-the-treatment-of-AGA-in-women-and-in-men.pdf
    reference_title: https://generolon.com/img/articles/Evidence-based-guideline-for-the-treatment-of-AGA-in-women-and-in-men.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: By the age of 70 or beyond, 80% of Caucasian men and up to 40% of women have signs of AGA.
    explanation: The guideline summarizes an age-specific estimate from prior epidemiology.
- population: Women, Caucasian
  measure_type: POINT_PREVALENCE
  prevalence_class: COMMON
  notes: A survey of 1,006 Caucasian women describes female-pattern hair loss as common with increasing occurrence in adult life. The S3 guideline summarizes up to 40% by age70 or later; age, ascertainment and case definition vary, so no uniform cohort rate is assigned.
  evidence:
  - reference: PMID:11231244
    reference_title: Incidence of female androgenetic alopecia (female pattern alopecia).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Female androgenetic alopecia is quite common beginning in the late 20s and reaching its peak after 50 years of age.
    explanation: The qualitative frequency and age course in women.
    quote_role: PRIMARY_RESULT
  - reference: url:https://generolon.com/img/articles/Evidence-based-guideline-for-the-treatment-of-AGA-in-women-and-in-men.pdf
    reference_title: https://generolon.com/img/articles/Evidence-based-guideline-for-the-treatment-of-AGA-in-women-and-in-men.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: By the age of 70 or beyond, 80% of Caucasian men and up to 40% of women have signs of AGA.
    explanation: This review estimate is age- and population-specific rather than a universal female lifetime rate.
clinical_trials:
- name: NCT05888922
  phase: PHASE_III
  status: ACTIVE_NOT_RECRUITING
  description: International, multicentre, randomized, double-blind phase III trial of oral minoxidil 1 mg once daily in women with androgenetic alopecia, double-dummy controlled against both placebo and topical 2 percent minoxidil solution, with hair density by photography as the efficacy readout and blood pressure, ECG and hypertrichosis as the safety readouts over up to 36 weeks. Planned enrolment about 520. The registered test of the oral route that is currently used off-label; registry status active, not recruiting, as of September 2026.
  target_phenotypes:
  - preferred_term: Diffuse central scalp thinning (Ludwig pattern)
    term:
      id: HP:0002209
      label: Sparse scalp hair
  evidence:
  - reference: clinicaltrials:NCT05888922
    reference_title: International Phase III, Multi Center, Randomized, Double Blind, Placebo and Active Controlled and Parallel Group Clinical Trial to Evaluate the Efficacy and Safety of Oral Minoxidil 1 mg in Female Patients With Androgenetic Alopecia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The main questions to answer are to know about that minoxidil 1mg is as effective as minoxidil 2% topical solution (comparator product) and is more effective than placebo; and to ensure treatment with oral minoxidil is safe.
    explanation: 'The registered objectives: non-inferiority to topical minoxidil, superiority to placebo, and safety of the oral route in women.'
    quote_role: BACKGROUND
  - reference: clinicaltrials:NCT05888922
    reference_title: International Phase III, Multi Center, Randomized, Double Blind, Placebo and Active Controlled and Parallel Group Clinical Trial to Evaluate the Efficacy and Safety of Oral Minoxidil 1 mg in Female Patients With Androgenetic Alopecia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'At the visits, the following examinations will be performed: photos of the hair will be taken to determine hair density, assessment of changes in scalp hair growth, measurement of blood pressure, pulse, and body temperature, a physical examination, blood withdrawal to determine any abnormalities in the blood, urine sampling and analysis, performance of ECG, and evaluation of hypertrichosis (i.e., excessive hair growth over the body).'
    explanation: The efficacy and safety readouts, which cover exactly the concerns (blood pressure, ECG, hypertrichosis) that the off-label use raises.
    quote_role: BACKGROUND
- name: NCT07529977
  phase: PHASE_III
  status: NOT_RECRUITING
  description: Phase 3, randomized, double-blind, placebo-controlled multicentre trial in Brazil of N1087, an oral minoxidil formulation titrated over 8 weeks to a maximum tolerated dose not exceeding 5 mg and then continued for 16 weeks, in men aged 18 to 60 with Norwood-Hamilton 3V, 4 or 5 disease, randomized 2 to 1 against placebo. The primary outcome is the change in non-vellus hair density in a vertex target area at 24 weeks by digital phototrichogram. Planned enrolment about 372; registry status not yet recruiting as of September 2026.
  target_phenotypes:
  - preferred_term: Frontotemporal hairline recession
    term:
      id: HP:0002292
      label: Frontal balding
  - preferred_term: Vellus-like miniaturized scalp hair
    term:
      id: HP:0002213
      label: Fine hair
  evidence:
  - reference: clinicaltrials:NCT07529977
    reference_title: A Phase 3, Prospective, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Clinical Trial to Evaluate the Efficacy and Safety of N1087 in Male Participants With Androgenetic Alopecia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The main purpose of the study is to assess whether oral minoxidil improves hair growth. The primary outcome measure is the change from baseline in the density of non-vellus hairs in a defined target area of the scalp (vertex) after 24 weeks of treatment, measured using digital phototrichogram analysis.
    explanation: Identifies N1087 as oral minoxidil and states the primary endpoint, non-vellus hair density, which is the clinical inverse of miniaturization.
    quote_role: BACKGROUND
  - reference: clinicaltrials:NCT07529977
    reference_title: A Phase 3, Prospective, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Clinical Trial to Evaluate the Efficacy and Safety of N1087 in Male Participants With Androgenetic Alopecia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: During the first 8 weeks, the dose will be gradually increased (titration period) up to a maximum tolerated dose, not exceeding 5 mg. Participants will then continue treatment at the maximum tolerated dose for the remaining 16 weeks.
    explanation: The titrated dosing scheme and the 5 mg ceiling.
    quote_role: BACKGROUND
- name: NCT06527365
  phase: PHASE_II
  status: ACTIVE_NOT_RECRUITING
  description: Open-label, multicentre phase 2 study of VDPHL01, an investigational oral tablet, given once daily as 8.5 mg to men and once or twice daily as 4.5 mg to women with androgenetic alopecia for 12 months, with 11 visits over about 13 months. Planned enrolment about 70. The uncontrolled safety and dose-exposure arm of the VDPHL01 programme; registry status active, not recruiting, as of September 2026.
  target_phenotypes:
  - preferred_term: Androgenetic (patterned) alopecia
    term:
      id: HP:0001596
      label: Alopecia
  evidence:
  - reference: clinicaltrials:NCT06527365
    reference_title: An Open-Label Multi-Dose Study to Evaluate the Safety and Efficacy of VDPHL01 in Male and Female Subjects With Androgenetic Alopecia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: VDPHL01 8.5 mg Tablets for males and VDPHL01 4.5 mg Tablets for females are an investigational oral drug to treat male and female pattern baldness.
    explanation: The agent, its sex-specific doses and its oral route as registered.
    quote_role: BACKGROUND
  - reference: clinicaltrials:NCT06527365
    reference_title: An Open-Label Multi-Dose Study to Evaluate the Safety and Efficacy of VDPHL01 in Male and Female Subjects With Androgenetic Alopecia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Male subjects that meet the study eligibility criteria will be administered VDPHL01 once daily for 12 months. Female subjects that meet the study eligibility criteria will be administered VDPHL01 either once or twice daily for 12 months.
    explanation: The open-label dosing schedule and duration.
    quote_role: BACKGROUND
- name: NCT06724614
  phase: PHASE_III
  status: ACTIVE_NOT_RECRUITING
  description: 'Randomized, double-blind, placebo-controlled, multicentre study of VDPHL01 8.5 mg tablets once daily in men with androgenetic alopecia: a placebo-controlled period covering the first seven visits followed by an open treatment extension in which all subjects receive active drug, about 13 months in all. Planned enrolment about 480. ClinicalTrials.gov registers the study under the combined designation Phase 2/Phase 3; the schema holds one value, so it is recorded as PHASE_III, the pivotal designation shared by its identically titled sibling NCT06972264. Registry status active, not recruiting, as of September 2026.'
  target_phenotypes:
  - preferred_term: Frontotemporal hairline recession
    term:
      id: HP:0002292
      label: Frontal balding
  evidence:
  - reference: clinicaltrials:NCT06724614
    reference_title: A Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Multi-dose Study to Evaluate the Efficacy and Safety of VDPHL01 in Male Subjects With Androgenetic Alopecia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The first 7 visits will be part of the placebo-controlled period. The next 3 visits will be part of the treatment extension phase. All subjects will receive active drug in the treatment extension phase.
    explanation: The placebo-controlled period followed by the open extension.
    quote_role: BACKGROUND
  - reference: clinicaltrials:NCT06724614
    reference_title: A Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Multi-dose Study to Evaluate the Efficacy and Safety of VDPHL01 in Male Subjects With Androgenetic Alopecia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: VDPHL01 8.5 mg Tablet is an investigational oral drug to treat male pattern baldness.
    explanation: The agent and dose under test in men.
    quote_role: BACKGROUND
- name: NCT06972264
  phase: PHASE_III
  status: ACTIVE_NOT_RECRUITING
  description: Second randomized, double-blind, placebo-controlled, multicentre phase 3 study of VDPHL01 8.5 mg tablets in men with androgenetic alopecia, about 13 months with 11 visits, registered under the same title as NCT06724614. Planned enrolment about 480. Registry status active, not recruiting, as of September 2026.
  target_phenotypes:
  - preferred_term: Frontotemporal hairline recession
    term:
      id: HP:0002292
      label: Frontal balding
  evidence:
  - reference: clinicaltrials:NCT06972264
    reference_title: A Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Multi-dose Study to Evaluate the Efficacy and Safety of VDPHL01 in Male Subjects With Androgenetic Alopecia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: This multi-center, double blind, study will last about 13 months and includes 11 study visits (screening, baseline (day 1), week 2, month 1, month 2, month 4, month 6, month 8, month 10, month 12, month 13).
    explanation: Design, duration and visit schedule as registered.
    quote_role: BACKGROUND
- name: NCT07146022
  phase: PHASE_III
  status: ACTIVE_NOT_RECRUITING
  description: Randomized, double-blind, placebo-controlled, multicentre phase 3 study of VDPHL01 in women with androgenetic alopecia, about 13 months with 11 visits, the female counterpart of the two male VDPHL01 phase 3 studies. Planned enrolment about 552. Registry status active, not recruiting, as of September 2026.
  target_phenotypes:
  - preferred_term: Diffuse central scalp thinning (Ludwig pattern)
    term:
      id: HP:0002209
      label: Sparse scalp hair
  evidence:
  - reference: clinicaltrials:NCT07146022
    reference_title: A Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Multi-Dose Study to Evaluate the Efficacy and Safety of VDPHL01 in Female Subjects With Androgenetic Alopecia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: This study will evaluate the safety and efficacy of VDPHL01 in female subjects with Androgenetic Alopecia (AGA).
    explanation: The registered objective in the female population.
    quote_role: BACKGROUND
  - reference: clinicaltrials:NCT07146022
    reference_title: A Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Multi-Dose Study to Evaluate the Efficacy and Safety of VDPHL01 in Female Subjects With Androgenetic Alopecia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: VDPHL01 is an investigational oral drug to treat AGA.
    explanation: The agent and route.
    quote_role: BACKGROUND
- name: NCT07563036
  phase: NOT_APPLICABLE
  status: RECRUITING
  description: Prospective single-arm, pre-post mechanistic study (Kasr El Aini Hospital, about 25 patients) measuring tissue Janus kinase 2 expression in balding against non-balding scalp at baseline and again in balding scalp after 3 months of topical minoxidil 5 percent, with trichoscopic parameters as the clinical readout. Not a phase-classified drug trial; it tests whether a JAK2 signal exists in balding scalp and whether minoxidil moves it, and the record carries no outcome results. Registry status recruiting as of September 2026.
  target_phenotypes:
  - preferred_term: Androgenetic (patterned) alopecia
    term:
      id: HP:0001596
      label: Alopecia
  evidence:
  - reference: clinicaltrials:NCT07563036
    reference_title: Assessment of Janus Kinase 2 Expression in Patients With Androgenic Alopecia and Its Modulation by Topical Minoxidil Therapy.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: This prospective single-arm pre-post interventional study aims to assess tissue Janus Kinase 2 (JAK2) expression in patients with androgenetic alopecia by comparing balding and non-balding scalp at baseline, and to evaluate changes in JAK2 expression in balding scalp after 3 months of topical minoxidil 5% therapy.
    explanation: Design, comparison and intervention as registered.
    quote_role: BACKGROUND
  - reference: clinicaltrials:NCT07563036
    reference_title: Assessment of Janus Kinase 2 Expression in Patients With Androgenic Alopecia and Its Modulation by Topical Minoxidil Therapy.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Clinical response will be assessed using standardized trichoscopic parameters.
    explanation: The clinical readout is trichoscopic, matching the diagnostic features recorded in this entry.
    quote_role: BACKGROUND
discussions:
- discussion_id: aga_fphl_androgen_dependence
  prompt: Is female pattern hair loss androgen-dependent at all, and if so through the same dermal papilla mechanism as the male disease?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - has_subtypes#Female pattern hair loss
  - pathophysiology#Dihydrotestosterone-Androgen Receptor Signaling
  rationale: Androgen-related tissue differences and clinical responses do not establish identical mechanisms across all female-pattern populations. Most affected women have normal circulating androgens. The negative 1-mg finasteride trial in postmenopausal women is dose- and population-specific. A 2025 randomized spironolactone add-on pilot now exists, but primary hair-count differences were not significant and the study was small. Larger trials with prespecified endocrine and tissue strata are needed to identify who benefits and whether response is mediated by the same dermal-papilla pathways as in male-pattern disease.
  evidence:
  - reference: PMID:12573818
    reference_title: Androgens and alopecia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: In contrast to its beneficial effects in men, finasteride did not improve hair growth in postmenopausal women with FPHL.
    explanation: The null result applies to the tested postmenopausal population and regimen.
  - *id011
  proposed_experiments:
  - experiment_id: aga_fphl_antiandrogen_rct
    name: Confirmatory stratified antiandrogen trial in female-pattern hair loss
    description: A larger trial could use prespecified androgen-status and tissue-expression strata, standardized background therapy and blinded hair-density outcomes to test heterogeneity of response. This would extend, rather than precede, the small 2025 placebo-controlled adjunct trial.
- discussion_id: aga_mouse_model_mismatch
  prompt: Do mouse models of hair growth inhibition, including mice treated with dihydrotestosterone and mice overexpressing prostaglandin synthase, model androgenetic alopecia, or only individual mediators of it?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Follicular Miniaturization
  - animal_models#K14-Ptgs2 mouse with altered skin prostanoids
  - animal_models#Topical PGD2 challenge in prostaglandin-receptor knockout mice
  rationale: The cited mouse interventions isolate selected mechanisms rather than reproduce human polygenic scalp-pattern disease. K14-Ptgs2 alters multiple prostanoids; topical PGD2 requires Gpr44 for hair-length inhibition but does not induce early catagen; injected IL6 is a separate cycle perturbation. Human follicle culture uses terminal face/brow hair, and the stem/progenitor paper demonstrates functional reconstitution with mouse cells, not rescue of patient scalp stem cells. Transfer between systems must preserve these distinctions.
  evidence:
  - *id008
  - *id009
  - *id010
  proposed_experiments:
  - experiment_id: aga_humanized_scalp_xenograft
    name: Human balding and non-balding scalp xenografts on immunodeficient mice under controlled androgen
    description: Graft paired frontal and occipital scalp from the same donors onto immunodeficient mice, castrated or supplemented with dihydrotestosterone, and follow terminal-to-vellus ratio and progenitor markers over successive cycles, so that the regional human program is studied in vivo without relying on mouse follicles.
- discussion_id: aga_microinflammation_cause_or_consequence
  prompt: Is perifollicular microinflammation and fibrosis a cause of follicular miniaturization, a cofactor that accelerates it, or a consequence of it?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Perifollicular Inflammation
  - pathophysiology#Perifollicular Fibrosis
  rationale: Small and selected biopsy studies show inflammation and sheath remodeling associated with AGA, but do not establish temporal direction or a treatment-responsive causal pathway. In one 44-person minoxidil subset, regrowth was observed in 55% with significant inflammation versus 77% without, not a halving. Scarring fibrosing alopecia in a pattern distribution is an important differential diagnosis rather than proof that all nonscarring AGA inevitably progresses to follicular destruction.
  evidence:
  - reference: PMID:12213548
    reference_title: Molecular mechanisms of androgenetic alopecia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Since the clinical success rate of treatment of AGA with modulators of androgen metabolism or hair growth promoters is limited, sustained microscopic follicular inflammation with connective tissue remodeling, eventually resulting in permanent hair loss, is considered a possible cofactor in the complex etiology of AGA.
    explanation: The current status, a possible cofactor, is the gap.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:1390168
    reference_title: 'Characterization of inflammatory infiltrates in male pattern alopecia: implications for pathogenesis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The data suggest that progressive fibrosis of the perifollicular sheath occurs in lesions of pattern alopecia, and may begin with T-cell infiltration of follicular stem cell epithelium.
    explanation: The causal proposal, framed as may, from the histological study.
    quote_role: PRIMARY_RESULT
  proposed_experiments:
  - experiment_id: aga_serial_biopsy_inflammation
    name: Serial biopsies of transitional scalp with follicle-level tracking of infiltrate and terminal-to-vellus status
    description: Biopsy the same transitional zone at intervals, mapping individual follicular units, to test whether T-cell infiltration and sheath thickening precede the drop in terminal-to-vellus ratio in the same unit or follow it, and whether follicles that miniaturize without infiltrate exist.
- discussion_id: aga_risk_allele_function
  prompt: What does the AR/EDA2R risk haplotype, or any of the several hundred autosomal risk alleles, actually do to the scalp follicle?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Polygenic Susceptibility
  rationale: Susceptibility signals nominate AR/EDA2R and many autosomal candidates, but the cited association and expression studies do not establish most allele-specific mechanisms. Absence of statistical AR-by-20p11 interaction is not proof of biochemical androgen independence. The 2017 eQTL overlap uses LD-based coincidence in healthy occipital follicles, not formal causal colocalization; pathway enrichments are candidate interpretations. Polygenic scores distinguish selected phenotypic categories but have not established prospective clinical decision benefit across populations.
  evidence:
  - reference: PMID:18849994
    reference_title: Susceptibility variants for male-pattern baldness on chromosome 20p11.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: No interaction was detected with the X-chromosomal androgen receptor locus, suggesting that the 20p11 locus has a role in a yet-to-be-identified androgen-independent pathway.
    explanation: A major locus whose pathway is explicitly unidentified.
    quote_role: PRIMARY_RESULT
  - reference: PMID:15902657
    reference_title: Genetic variation in the human androgen receptor gene is the major determinant of common early-onset androgenetic alopecia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The investigation of a large number of genetic variants covering the AR locus suggests that a polyglycine-encoding GGN repeat in exon 1 is a plausible candidate for conferring the functional effect.
    explanation: The functional variant at the strongest locus remains a candidate.
    quote_role: PRIMARY_RESULT
  proposed_experiments:
  - experiment_id: aga_ar_locus_allelic_expression
    name: Allele-specific expression and chromatin accessibility of AR and EDA2R in scalp dermal papilla from risk-haplotype carriers
    description: In dermal papilla cells from frontal and occipital scalp of carriers and non-carriers, measure allele-specific AR and EDA2R expression, map accessible regulatory elements across the linkage block, and edit candidate variants in immortalized balding dermal papilla lines to test which changes receptor level and androgen-induced DKK1, TGFB1 and IL6 output.
- discussion_id: aga_sult1a1_minoxidil_response
  prompt: Does follicular SULT1A1 sulfotransferase activity predict the response to topical minoxidil, and could it be used to select patients or to rescue non-responders?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - treatments#Topical minoxidil
  rationale: Follicular sulfotransferase activity is a candidate minoxidil-response biomarker. A 2015 study prospectively assayed 15 participants before topical treatment and reported 100% sensitivity and 71% specificity against a later photographic response classification. Its combined 70-person calculation gave a 95.9% negative predictive value assuming a 40% response prevalence. This is not universal test accuracy, an allele-specific loss-of-function result or evidence that assay-guided prescribing improves outcomes. Broader external validation and prospective clinical utility remain unresolved.
  evidence:
  - reference: url:https://prtimes.jp/a/?f=d59603-106-d6c9c40ba4f09ed7d1658c32d4f991e5.pdf
    reference_title: https://prtimes.jp/a/?f=d59603-106-d6c9c40ba4f09ed7d1658c32d4f991e5.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: A total of 15 patients (eight male, seven female) were included in our analysis of minoxidil response testing.
    explanation: The small prospective study updates the previous incorrect claim that no prospective validation existed.
  - reference: url:https://prtimes.jp/a/?f=d59603-106-d6c9c40ba4f09ed7d1658c32d4f991e5.pdf
    reference_title: https://prtimes.jp/a/?f=d59603-106-d6c9c40ba4f09ed7d1658c32d4f991e5.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: sensitivity of 100% and a speciﬁcity of 71% (Student’s t-test p < 0.005).
    explanation: Performance is estimated in the small prospective subset; no clinical-utility trial follows.
  proposed_experiments:
  - experiment_id: aga_sult1a1_stratified_minoxidil_trial
    name: External validation and clinical-utility trial of follicular sulfotransferase testing
    description: Use an independent cohort and prespecified threshold to test calibration across populations, then compare assay-guided care with usual care. Genotype effects should be measured separately rather than inferred from enzymatic activity.
differential_diagnoses:
- name: Telogen effluvium
  description: Diffuse shedding without patterned miniaturization, often with a precipitant three months earlier. Distinguished by a positive pull test across the whole scalp, absence of hair-diameter variability, and a normal terminal-to-vellus ratio on biopsy. The two commonly coexist in women.
- name: Alopecia areata
  description: Autoimmune, non-scarring, and typically patchy, with exclamation-mark hairs, black dots and yellow dots on trichoscopy and a peribulbar lymphocytic infiltrate rather than miniaturization. A diffuse variant can mimic the female pattern.
- name: Frontal fibrosing alopecia and lichen planopilaris
  description: Scarring alopecias in which follicular ostia are lost. Frontal fibrosing alopecia recedes the frontal hairline band-like with loss of eyebrows, and a pattern-distributed fibrosing variant of lichen planopilaris is the main scarring mimic of the female pattern; both need biopsy when suspected.
- name: Traction alopecia and trichotillomania
  description: Mechanical causes with a distribution that follows hairstyle or hand, and with broken hairs of varying length in trichotillomania.
- name: Hyperandrogenic disorders in women
  description: Polycystic ovary syndrome, androgen-secreting tumours and adrenal disorders can produce a male-type pattern with hirsutism, acne and menstrual disturbance; these signs, not the hair loss itself, prompt endocrine testing.
classifications:
  harrisons_chapter:
  - classification_value: DERMATOLOGY
references:
- reference: PMID:10882953
  title: 'Current understanding of androgenetic alopecia. Part II: clinical aspects and treatment.'
- reference: PMID:11231244
  title: Incidence of female androgenetic alopecia (female pattern alopecia).
- reference: PMID:11231320
  title: Polymorphism of the androgen receptor gene is associated with male pattern baldness.
- reference: PMID:11511857
  title: Possible mechanisms of miniaturization during androgenetic alopecia or pattern hair loss.
- reference: PMID:1188424
  title: 'Male pattern baldness: classification and incidence.'
- reference: PMID:12174065
  title: 'Follicular unit extraction: minimally invasive surgery for hair transplantation.'
- reference: PMID:12196747
  title: A randomized clinical trial of 5% topical minoxidil versus 2% topical minoxidil and placebo in the treatment of androgenetic alopecia in men.
- reference: PMID:12213548
  title: Molecular mechanisms of androgenetic alopecia.
- reference: PMID:12397096
  title: 'Androgen-inducible TGF-beta1 from balding dermal papilla cells inhibits epithelial cell growth: a clue to understand paradoxical effects of androgen on human hair growth.'
- reference: PMID:12573818
  title: Androgens and alopecia.
- reference: PMID:12673073
  title: 'Association between smoking and hair loss: another opportunity for health education against smoking?'
- reference: PMID:1390168
  title: 'Characterization of inflammatory infiltrates in male pattern alopecia: implications for pathogenesis.'
- reference: PMID:14996087
  title: 'Minoxidil: mechanisms of action on hair growth.'
- reference: PMID:15787815
  title: Treatment of female pattern hair loss with oral antiandrogens.
- reference: PMID:15902657
  title: Genetic variation in the human androgen receptor gene is the major determinant of common early-onset androgenetic alopecia.
- reference: PMID:16039422
  title: 'Follicular unit transplantation: 2005.'
- reference: PMID:16382668
  title: 'Female pattern hair loss and its relationship to permanent/cicatricial alopecia: a new perspective.'
- reference: PMID:17110217
  title: 'The importance of dual 5alpha-reductase inhibition in the treatment of male pattern hair loss: results of a randomized placebo-controlled study of dutasteride versus finasteride.'
- reference: PMID:17657240
  title: Dihydrotestosterone-inducible dickkopf 1 from balding dermal papilla cells causes apoptosis in follicular keratinocytes.
- reference: PMID:17989730
  title: Premature senescence of balding dermal papilla cells in vitro is associated with p16(INK4a) expression.
- reference: PMID:18385763
  title: EDA2R is associated with androgenetic alopecia.
- reference: PMID:18849991
  title: Male-pattern baldness susceptibility locus at 20p11.
- reference: PMID:18849994
  title: Susceptibility variants for male-pattern baldness on chromosome 20p11.
- reference: PMID:20426781
  title: 'Association of androgenetic alopecia with metabolic syndrome in men: a community-based survey.'
- reference: PMID:20619491
  title: 'Androgenetic alopecia and cardiovascular risk factors in men and women: a comparative study.'
- reference: PMID:21206086
  title: Bald scalp in men with androgenetic alopecia retains hair follicle stem cells but lacks CD200-rich and CD34-positive hair follicle progenitor cells.
- reference: PMID:21881585
  title: Dihydrotestosterone-inducible IL-6 inhibits elongation of human hair shafts by suppressing matrix cell proliferation and promotes regression of hair follicles in mice.
- reference: PMID:22283397
  title: Hair follicle stem cell differentiation is inhibited through cross-talk between Wnt/β-catenin and androgen signalling in dermal papilla cells from patients with androgenetic alopecia.
- reference: PMID:22440736
  title: Prostaglandin D2 inhibits hair growth and is elevated in bald scalp of men with androgenetic alopecia.
- reference: PMID:22693459
  title: Six novel susceptibility Loci for early-onset androgenetic alopecia and their unexpected association with common diseases.
- reference: PMID:23358095
  title: 'Androgenetic alopecia: identification of four genetic risk loci and evidence for the contribution of WNT signaling to its etiology.'
- reference: PMID:23960389
  title: 'A randomized evaluator blinded study of effect of microneedling in androgenetic alopecia: a pilot study.'
- reference: PMID:24474647
  title: 'Efficacy and safety of a low-level laser device in the treatment of male and female pattern hair loss: a multicenter, randomized, sham device-controlled, double-blind study.'
- reference: PMID:27060448
  title: Differential Expression between Human Dermal Papilla Cells from Balding and Non-Balding Scalps Reveals New Candidate Genes for Androgenetic Alopecia.
- reference: PMID:28196072
  title: Genetic prediction of male pattern baldness.
- reference: PMID:28272467
  title: Meta-analysis identifies novel risk loci and yields systematic insights into the biology of male-pattern baldness.
- reference: PMID:28349362
  title: 'Androgenetic alopecia: a review.'
- reference: PMID:30573740
  title: Dissection of genetic variation and evidence for pleiotropy in male pattern baldness.
- reference: PMID:30882509
  title: Platelet-Rich Plasma as a Treatment for Androgenetic Alopecia.
- reference: PMID:34634163
  title: 'Efficacy and safety of topical finasteride spray solution for male androgenetic alopecia: a phase III, randomized, controlled clinical trial.'
- reference: PMID:38610726
  title: 'Trichoscopy of Androgenetic Alopecia: A Systematic Review.'
- reference: PMID:39192534
  title: 'Association between psychosocial distress, sexual disorders, self-esteem and quality of life with male androgenetic alopecia: a population-based study with men at age 46.'
- reference: PMID:40978669
  title: 'Efficacy and safety of oral spironolactone for female pattern hair loss in premenopausal women: a randomized, double-blind, placebo-controlled, parallel-group pilot study.'
- reference: PMID:40986632
  title: 'A Canadian Consensus on Androgenetic Alopecia: Approach and Management.'
- reference: PMID:41606541
  title: 'Risk factors for androgenetic alopecia: a systematic review and meta-analysis.'
- reference: PMID:7962310
  title: The effects of finasteride (Proscar) on hair growth, hair cycle stage, and serum testosterone and dihydrotestosterone in adult male and female stumptail macaques (Macaca arctoides).
- reference: PMID:8496421
  title: Diagnostic and predictive value of horizontal sections of scalp biopsy specimens in male pattern androgenetic alopecia.
- reference: PMID:8977424
  title: Inhibition of hair growth by testosterone in the presence of dermal papilla cells from the frontal bald scalp of the postpubertal stumptailed macaque.
- reference: PMID:921894
  title: Classification of the types of androgenetic alopecia (common baldness) occurring in the female sex.
- reference: PMID:9284093
  title: Different levels of 5alpha-reductase type I and II, aromatase, and androgen receptor in hair follicles of women and men with androgenetic alopecia.
- reference: PMID:9496234
  title: Balding hair follicle dermal papilla cells contain higher levels of androgen receptors than those from non-balding scalp.
- reference: PMID:9777765
  title: Finasteride in the treatment of men with androgenetic alopecia. Finasteride Male Pattern Hair Loss Study Group.
- reference: PMID:9865198
  title: Prevalence of male pattern hair loss in 18-49 year old men.
- reference: clinicaltrials:NCT05888922
  title: International Phase III, Multi Center, Randomized, Double Blind, Placebo and Active Controlled and Parallel Group Clinical Trial to Evaluate the Efficacy and Safety of Oral Minoxidil 1 mg in Female Patients With Androgenetic Alopecia
- reference: clinicaltrials:NCT06527365
  title: An Open-Label Multi-Dose Study to Evaluate the Safety and Efficacy of VDPHL01 in Male and Female Subjects With Androgenetic Alopecia
- reference: clinicaltrials:NCT06724614
  title: A Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Multi-dose Study to Evaluate the Efficacy and Safety of VDPHL01 in Male Subjects With Androgenetic Alopecia
- reference: clinicaltrials:NCT06972264
  title: A Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Multi-dose Study to Evaluate the Efficacy and Safety of VDPHL01 in Male Subjects With Androgenetic Alopecia
- reference: clinicaltrials:NCT07146022
  title: A Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Multi-Dose Study to Evaluate the Efficacy and Safety of VDPHL01 in Female Subjects With Androgenetic Alopecia
- reference: clinicaltrials:NCT07529977
  title: A Phase 3, Prospective, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Clinical Trial to Evaluate the Efficacy and Safety of N1087 in Male Participants With Androgenetic Alopecia.
- reference: clinicaltrials:NCT07563036
  title: Assessment of Janus Kinase 2 Expression in Patients With Androgenic Alopecia and Its Modulation by Topical Minoxidil Therapy.
- reference: url:https://bhns.org.uk/ccs_files/web_data/Resources/Guidelines/european%20S1%20AGA%20guidelien.pdf
  title: https://bhns.org.uk/ccs_files/web_data/Resources/Guidelines/european%20S1%20AGA%20guidelien.pdf
- reference: url:https://generolon.com/img/articles/Evidence-based-guideline-for-the-treatment-of-AGA-in-women-and-in-men.pdf
  title: https://generolon.com/img/articles/Evidence-based-guideline-for-the-treatment-of-AGA-in-women-and-in-men.pdf
- reference: url:https://prtimes.jp/a/?f=d59603-106-d6c9c40ba4f09ed7d1658c32d4f991e5.pdf
  title: https://prtimes.jp/a/?f=d59603-106-d6c9c40ba4f09ed7d1658c32d4f991e5.pdf
- reference: url:https://www.ema.europa.eu/en/documents/referral/finasteride-dutasteride-containing-medicinal-products-article-31-referral-measures-minimise-risk-suicidal-thoughts-finasteride-dutasteride-medicines_en.pdf
  title: https://www.ema.europa.eu/en/documents/referral/finasteride-dutasteride-containing-medicinal-products-article-31-referral-measures-minimise-risk-suicidal-thoughts-finasteride-dutasteride-medicines_en.pdf
- reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11007651/
  title: 'Oral Minoxidil vs Topical Minoxidil for Male Androgenetic Alopecia: A Randomized Clinical Trial - PMC'
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK430924/
  title: Androgenetic Alopecia - StatPearls - NCBI Bookshelf
  tags:
  - StatPearls
- reference: url:https://www.newswise.com/pdf_docs/173213268899494_jamadermatology_akiska_2024_cs_240009_1732051708.84641%20%281%29.pdf
  title: https://www.newswise.com/pdf_docs/173213268899494_jamadermatology_akiska_2024_cs_240009_1732051708.84641%20%281%29.pdf
experimental_models:
- name: Macaque dermal-papilla and outer-root-sheath coculture
  experimental_model_type: CO_CULTURE
  cell_source: Dermal papilla and outer-root-sheath cells from adult frontal/occipital and juvenile frontal macaque scalp
  description: Testosterone inhibited outer-root-sheath cell proliferation only with adult bald-frontal dermal papilla cells in the cited coculture. The androgen-receptor blocker RU 58841 antagonized inhibition. This model tests site- and age-dependent paracrine response; it does not prove absence of receptors in every unaffected human follicle.
  evidence:
  - &id012
    reference: PMID:8977424
    reference_title: Inhibition of hair growth by testosterone in the presence of dermal papilla cells from the frontal bald scalp of the postpubertal stumptailed macaque.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Testosterone-induced inhibition of outer root sheath cell proliferation occurred only in coculture with dermal papilla cells derived from the bald scalps of adult macaques but not with dermal papilla cells from the hairy occipital scalps of adult macaques or the prebald frontal scalps of juvenile macaques.
    explanation: Regional and age-specific response was tested in macaque cell coculture, not inferred from intact-animal hair weight.
  - reference: PMID:8977424
    reference_title: Inhibition of hair growth by testosterone in the presence of dermal papilla cells from the frontal bald scalp of the postpubertal stumptailed macaque.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Furthermore, RU 58841, an androgen receptor blocker, antagonized this testosterone-elicited inhibition.
    explanation: Antagonism supports receptor involvement within the cell preparation.
  modeled_mechanisms:
  - target: Dihydrotestosterone-Androgen Receptor Signaling
    relationship: PERTURBS
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: Testosterone and an AR blocker probe androgen-dependent epithelial inhibition mediated by dermal papilla cells.
    limitations: The applied androgen is testosterone; DHT flux and the entire human clinical mechanism are not directly measured.
    evidence:
    - *id012
- name: AR-transfected human dermal-papilla and keratinocyte coculture
  experimental_model_type: CO_CULTURE
  cell_source: Cultured balding-derived human dermal papilla cells with keratinocytes
  description: Native cultured dermal papilla cells initially showed no significant androgen-dependent inhibition. AR transfection restored the response, with increased TGF-beta1 secretion and antibody-sensitive keratinocyte growth suppression. The engineered receptor context limits extrapolation to untreated patient follicles.
  evidence:
  - reference: PMID:12397096
    reference_title: 'Androgen-inducible TGF-beta1 from balding dermal papilla cells inhibits epithelial cell growth: a clue to understand paradoxical effects of androgen on human hair growth.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: In this modified coculture, androgen significantly suppressed the growth of KCs by approximately 50%, indicating that overexpression of AR can restore the responsiveness of the DPCs to androgen in vivo.
    explanation: The growth effect occurs in the receptor-transfected preparation.
  - *id013
  modeled_mechanisms:
  - target: Increased TGF-Beta1 Secretion
    relationship: PERTURBS
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: Androgen exposure tests secreted TGF-beta1 in the modified coculture.
    limitations: AR overexpression restores culture responsiveness and may alter quantitative signaling.
    evidence:
    - *id013
  - target: Reduced Follicular Keratinocyte Proliferation
    relationship: MEASURES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Neutralizing TGF-beta1 reverses the coculture growth inhibition.
    limitations: Keratinocyte population growth is not direct measurement of chronic patient miniaturization.
    evidence:
    - reference: PMID:12397096
      reference_title: 'Androgen-inducible TGF-beta1 from balding dermal papilla cells inhibits epithelial cell growth: a clue to understand paradoxical effects of androgen on human hair growth.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: Moreover, the neutralizing anti-TGF-beta1 antibody reversed the androgen-elicited growth inhibition of KCs in a dose-dependent manner.
      explanation: Neutralization supports a TGF-beta1-dependent component.
- name: Human dermal-papilla Wnt and differentiation coculture
  experimental_model_type: CO_CULTURE
  cell_source: Human dermal papilla cells and follicular stem-cell preparations
  description: Androgen exposure altered beta-catenin/GSK3beta readouts in dermal papilla cells and reduced their ability to induce hair keratin expression in cocultured follicular cells. Wnt activation rescued that differentiation readout. The signaling measurement is in dermal papilla, and the experiment does not directly measure the marker-defined progenitor deficits in paired patient scalp.
  evidence:
  - *id014
  - *id015
  modeled_mechanisms:
  - target: Reduced Canonical Wnt Signaling in Dermal Papilla Cells
    relationship: PERTURBS
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: Androgen treatment alters the measured pathway state.
    limitations: Assay-specific signaling and differentiation readouts; no patient lineage tracing.
    evidence:
    - *id014
  - target: Impaired Follicular Epithelial Differentiation
    relationship: MEASURES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Hair keratin induction is used as a differentiation readout.
    limitations: Rescue in culture does not establish the complete human disease route.
    evidence:
    - *id015
- name: Human terminal follicle organ culture exposed to PGD2
  experimental_model_type: OTHER
  cell_source: Terminal anagen follicles from face/brow-lift tissue of adult women and men
  description: PGD2 and 15-dPGJ2 inhibited elongation in terminal follicle cultures from at least three donors per compound. The samples were not established miniaturized AGA scalp follicles. Human GPR44 involvement was inferred from agonist-potency correlation; receptor necessity was tested separately in mice. No clinical regrowth or human stem-cell rescue was demonstrated.
  evidence:
  - *id016
  - reference: PMID:22440736
    reference_title: Prostaglandin D2 inhibits hair growth and is elevated in bald scalp of men with androgenetic alopecia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: For hair-lengthening experiments, discarded tissue from face lifts, which contain terminal hair, was used.
    explanation: The follicle source is terminal hair from discarded face-lift tissue.
  modeled_mechanisms:
  - target: PGD2-Associated Hair Growth Inhibition
    relationship: PERTURBS
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Exogenous prostaglandin exposure reduces cultured hair elongation.
    limitations: Donor site, exposure concentration and short culture interval limit disease-level inference.
    evidence:
    - *id016
review_notes: Full review separates clinical association, experimental perturbation and unresolved human mediation. It corrects the PGD2/catagen and progenitor-function claims, regional receptor localization, GWAS variance denominators, cross-sectional severity terminology, trial endpoints, updated care and regulatory safety information. All new reference files were generated with just fetch-reference; no cache text was authored. Independent bounded source audits covered PGD2/stem cells, four genetics papers and care integration.

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