| Title | Authors | Year |
|---|---|---|
| Abstract A037: Coordinated activity between AR-V7 and glucocorticoid receptor drives resistance to androgen receptor signaling inhibition | Zhang et al. | 2025 |
Summary
Although no current peer-reviewed studies demonstrate the AR-V7–GR (glucocorticoid receptor) complex in hair or skin tissue, mechanistic parallels suggest this complex could exist under conditions of chronic stress and androgen deprivation.
In the scalp, dermal papilla and keratinocyte cells are both androgen-responsive and glucocorticoid-sensitive. If AR-V7 expression were induced by sustained cortisol exposure or by decreased DHT signaling, a cortisol-activated GR–AR-V7 heterodimer could hypothetically maintain the same stress-excitable state that canonical DHT–AR signaling produces—driving follicular miniaturization through oxidative and inflammatory signaling loops.
Established Facts
-
DHT–AR Signaling and Hair Loss:
- DHT activates AR in dermal papilla cells, inducing TGF-β, Dkk-1, and IL-6.
- These factors shorten the anagen phase, cause matrix-cell apoptosis, and progressively miniaturize the follicle.
- Local 5-α-reductase type II amplifies DHT conversion, and AR abundance is highest in androgen-sensitive scalp regions.
-
GR Expression in Skin:
- NR3C1 (GR) is expressed in keratinocytes, dermal papillae, and sebocytes.
- Cortisol influences epidermal differentiation, wound healing, and follicle cycling.
- Chronic glucocorticoid exposure or stress disrupts hair cycling and contributes to telogen effluvium and alopecia areata.
-
AR-V7 in Other Tissues:
- AR-V7 is documented in prostate and some epithelial cancers under androgen deprivation.
- It is constitutively active (lacking the ligand-binding domain) and can form complexes with GR to sustain transcription through GRE/ARE hybrid DNA sites.
Theoretical Mechanism in Hair Follicles
If AR-V7 expression occurs in follicular tissue, chronic cortisol could activate GR and recruit AR-V7 to chromatin, forming a cortisol-driven mimic of DHT signaling.
Hypothesized Pathway
Stress → ↑ Cortisol → GR activation → AR-V7–GR complex formation
↓
GRE/ARE hybrid activation → FKBP5↑, SGK1↑, TGF-β↑, Dkk-1↑
↓
Oxidative stress + inflammation → Follicular miniaturization
- GR provides ligand activation (cortisol).
- AR-V7 provides DNA-binding to androgenic loci.
- The hybrid complex could maintain androgenic transcription even in low-DHT conditions.
- Ionic excitability (ENaC/NKCC1/ADRB2 upregulation) and mitochondrial ROS generation would parallel the excitatory cascade observed in neurons within our stress-glutamate model.
Functional Prediction
| Feature | DHT–AR | Cortisol–GR–AR-V7 (Hypothetical) |
|---|---|---|
| Ligand | DHT | Cortisol |
| Pathway activation | AR full-length | GR with AR-V7 |
| Outcome | TGF-β, Dkk-1, IL-6 → miniaturization | Same downstream genes plus FKBP5/SGK1 stress amplification |
| Redox profile | High ROS, reduced antioxidant tone | High ROS from chronic stress signaling |
| System context | High androgen load | High stress load / low androgen |
Relation to the Stress–Glutamate–NR3C1 Model
- The follicle represents a peripheral excitatory microcircuit.
- DHT-AR activation corresponds to overdriven excitatory tone, analogous to glutamate overactivity in neurons.
- Under stress, if cortisol substitutes for DHT through GR–AR-V7 coupling, the same excitotoxic-style degeneration occurs causing progressive mitochondrial strain, calcium imbalance, and cell shrinkage.
- Chronic activation would trigger NR3C1 hypermethylation in follicular cells, recording the stress load epigenetically and stabilizing the miniaturized phenotype.
Evidence Status
| Aspect | Empirical Status |
|---|---|
| GR presence in hair/skin | Confirmed |
| DHT-AR miniaturization mechanism | Confirmed |
| AR-V7 expression in skin/hair | Unverified |
| AR-V7–GR complex in skin/hair | Unverified |
| GR–AR-V7 mimicry of androgen signaling | Demonstrated in prostate models only |
| Hypothesized functional equivalence in hair | Theoretical but mechanistically consistent |
Implications
If validated, this mechanism would unify:
- Stress-induced and androgenic alopecia as manifestations of the same NR3C1-driven excitatory overactivation.
- Androgen deprivation and cortisol elevation as interchangeable triggers of follicular regression.
- The idea that hair follicles “remember” stress epigenetically through NR3C1 methylation and persistent GR overexpression.
Experimental Predictions
- AR-V7 transcripts could appear in dermal papilla under chronic cortisol or anti-androgen exposure.
- Co-immunoprecipitation of AR-V7 and GR in cultured follicular cells would increase under stress-mimetic conditions.
- Cortisol + AR blockade should still upregulate TGF-β, SGK1, and FKBP5 in these cells, supporting hybrid signaling.
- Chronic GR activation should correlate with increased NR3C1 promoter methylation in miniaturized follicles.
Summary Insight
Hair loss may represent a peripheral form of excitotoxic stress: DHT and cortisol both drive the same NR3C1-linked transcriptional circuitry, through different receptor configurations. In the absence of DHT, the GR–AR-V7 complex could substitute for AR-FL, sustaining excitatory metabolism until oxidative failure leads to follicular miniaturization.