A hypothetical pathogenesis model for androgenic alopecia: clarifying the dihydrotestosterone paradox and rate-limiting recovery factors

Dr Daniel Fernandes Melo

Dermatologist, Professor of Trichology at Federal University of Rio de Janeiro (UERJ), Brazil

Commentary

This interesting article suggests an innovative explanation for the occurrence of one of the most common dermatologic complaints: hair loss due to androgenic alopecia. The author raises a new hypothesis model about its pathogenesis whilst attempts to approach some unanswered questions related to the dihydrotestosterone paradox and the limits for recovery.  The hypothesis still needs further investigation but seems an excellent pillar to sustain the research for new treatments and better outcomes.

Introduction

Androgenic alopecia (AGA) is a chronic progressive condition characterized as persistent and patterned hair thinning in scalp regions above the galea aponeurotica, affecting 80% of men and 50% of women throughout a lifetime, causing a stressful emotional impact for the patient. However, despite its prevalence and extensive study, there is no coherent pathology model describing its precursors, biological processes, and physiological response. The consensus is that androgenic alopecia is genetic and androgen-mediated by dihydrotestosterone, but some questions regarding dihydrotestosterone’s exact role still remain unanswered. Besides, there is no viable cure and treatments are not always considered completely satisfactory by the patients. 

Actually, there are still some unanswered questions in AGA pathology, as “If AGA-prone hair follicles are genetically programmed to sensitize to and miniaturize in the presence of DHT, then why doesn’t complete DHT attenuation lead to complete AGA recovery? If AGA incidence increases with age, why is this condition more common in elderly persons with relatively lower androgen production? Paradoxically, why is DHT associated with both AGA-prone hair follicle miniaturization and secondary body and facial hair growth? Why is AGA mostly isolated to areas above and immediately surrounding the GA?

Existing AGA pathology models do not explain any of these. There is a need for an alternative, evidence-based model for AGA pathogenesis, clarifying DHT's role, offering a mechanism behind the rate-limiting effects of androgen suppression in hair regrowth, and explaining the roles and relationships of other biomarkers in balding scalp tissues.

Hypothesis

The article argues that Androgenic alopecia is the result of a chronic scalp tension mediated by pubertal and post-pubertal skull bone growth and/or the overdevelopment and chronic contraction of muscles connected to the GA. This leads to a site-specific, pro-inflammatory cascade that upregulates signaling proteins and androgens involved in fibrosis and calcification pathogenesis, which results in a slow, persistent tissue remodeling – restricting follicle growth space and reducing oxygen and nutrient supply – finally causing the hair follicle miniaturization and pattern baldness.

Evaluation of hypothesis

The author took an investigative approach to build the pathology model – first cataloguing differences in balding versus non-balding AGA scalps, and then exploring association or causation between variables. Some of the questions that conducted the investigation were: Is fibrosis associative or causative in Androgenic Alopecia? Is capillary calcification a potential driver of microvascular insufficiency and thereby contributor to AGA-related hair thinning? How is androgen involved in AGA? If TGF-β1 is androgen-induced, why might TGF-β1 express more highly in AGA tissues versus secondary body and facial hair tissues? By mechanical tension? What factors may induce a GA-transmitted scalp tension? How can be explained the androgen-inflammation feedback loop? How can be explained the donor hair transplant survival rates? Why do estrogen-injected castrates experience significant hair recovery beyond what is observed from androgen inhibition alone?

Implications of Hypothesis

This model might be useful to understand the limitations of Finasteride and 5% Minoxidil, current Androgenic Alopecia treatment. While the hypothesis attempts to create a more robust AGA pathology model, more research is still needed for validation. One of the challenges is “Which came first: the fibrosis and calcification, or the AGA?” and identifying better AGA treatment targets.

Conclusion

This model allows for genetic influence during any step-process but refutes the belief that AGA-prone follicles are genetically programmed to become sensitive to DHT. Rather, the model implies that AGA-prone tissues are predisposed to respond to chronic tension-mediated inflammation by inducing DHT and androgen-mediated TGF-β1, which restructure the tissue – of which a symptom is hair loss.

The model also provides a rationale for unexplained phenomena in Androgenic Alopecia pathology, such as: AGA pattern, the reason DHT increases in AGA-prone scalp tissues, the mechanisms by which DHT is involved in AGA progression, why AGA is observed more often in elderly versus young people, why DHT is associated with body and facial hair growth and also AGA-related hair loss, and finally why androgen suppression stops AGA but does not regrow all hair.

The author suggests then that future research should focus on the use of mechanotransduction to potentially reverse AGA-related tissue remodeling. If the hypothesis is true, then reversing AGA tissue remodeling – rather than attenuating it, may be the first step to full recoveries.