A Hypothetical Pathogenesis Model for Androgenic Alopecia: Clarifying the Dihydrotestosterone Paradox and Rate-Limiting Recovery Factors

Med Hypotheses. 2018 Feb;111:73-81. doi: 10.1016/j.mehy.2017.12.027. Epub 2017 Dec 30.

Abstract

Androgenic alopecia, also known as pattern hair loss, is a chronic progressive condition that affects 80% of men and 50% of women throughout a lifetime. But despite its prevalence and extensive study, a coherent pathology model describing androgenic alopecia's precursors, biological step-processes, and physiological responses does not yet exist. While consensus is that androgenic alopecia is genetic and androgen-mediated by dihydrotestosterone, questions remain regarding dihydrotestosterone's exact role in androgenic alopecia onset. What causes dihydrotestosterone to increase in androgenic alopecia-prone tissues? By which mechanisms does dihydrotestosterone miniaturize androgenic alopecia-prone hair follicles? Why is dihydrotestosterone also associated with hair growth in secondary body and facial hair? Why does castration (which decreases androgen production by 95%) stop pattern hair loss, but not fully reverse it? Is there a relationship between dihydrotestosterone and tissue remodeling observed alongside androgenic alopecia onset? We review evidence supporting and challenging dihydrotestosterone's causal relationship with androgenic alopecia, then propose an evidence-based pathogenesis model that attempts to answer the above questions, account for additionally-suspected androgenic alopecia mediators, identify rate-limiting recovery factors, and elucidate better treatment targets. The hypothesis argues that: (1) chronic scalp tension transmitted from the galea aponeurotica induces an inflammatory response in androgenic alopecia-prone tissues; (2) dihydrotestosterone increases in androgenic alopecia-prone tissues as part of this inflammatory response; and (3) dihydrotestosterone does not directly miniaturize hair follicles. Rather, dihydrotestosterone is a co-mediator of tissue dermal sheath thickening, perifollicular fibrosis, and calcification - three chronic, progressive conditions concomitant with androgenic alopecia progression. These conditions remodel androgenic alopecia-prone tissues - restricting follicle growth space, oxygen, and nutrient supply - leading to the slow, persistent hair follicle miniaturization characterized in androgenic alopecia. If true, this hypothetical model explains the mechanisms by which dihydrotestosterone miniaturizes androgenic alopecia-prone hair follicles, describes a rationale for androgenic alopecia progression and patterning, makes sense of dihydrotestosterone's paradoxical role in hair loss and hair growth, and identifies targets to further improve androgenic alopecia recovery rates: fibrosis, calcification, and chronic scalp tension.

MeSH terms

  • Alopecia / etiology*
  • Alopecia / physiopathology*
  • Androgens / metabolism
  • Biomarkers / metabolism
  • Dihydrotestosterone / blood*
  • Disease Progression
  • Estrogens / therapeutic use
  • Female
  • Fibrosis / physiopathology
  • Hair / growth & development
  • Hormone Replacement Therapy
  • Humans
  • Inflammation
  • Male
  • Models, Theoretical
  • Scalp / metabolism
  • Transforming Growth Factor beta1 / metabolism

Substances

  • Androgens
  • Biomarkers
  • Estrogens
  • Transforming Growth Factor beta1
  • Dihydrotestosterone