How did this concept evolve?
The understanding of the hair follicle biology over the last 20 years established the fundamental role of the mesenchyme derived dermal papillae in the maintenance of the hair growth, with the multipotent epithelial stem cells at the bulge giving rise to proliferation and differentiation.
[14],
[15],
[16],
[17] Other autocrine, paracrine factors and signaling pathways are also involved in this cross-talk between the dermal papillae and the hair follicle stem cells.
[16],
[18],
[19]
Testosterone and other weaker androgens such as dehydroepiandrosterone and androstenedione are metabolized in many skin tissues. Testosterone can freely penetrate the cell membrane and is converted in the cytoplasm to dihydrotestosterone (DHT) by 5 α reductase (mainly Type II). The DHT strongly binds to androgen receptor (AR) and this complex is translocated to the nucleus, helped by the AR co activators. This results in target gene transcription and finally translation into genes which exert biological activity.
[20],
[21],
[22]
The cross-talk between the dermal papillae and the hair follicle cells which unfolds under the influence of androgens result from the secretion of many factors from the dermal papillae. These have autocrine effect on the dermal papillae itself and paracrine effect on the hair follicle epithelial cells.
[23] These factors include growth factors like Insulin like growth factor (IGF-1), basic fibroblast factor (bFGF), vascular endothelial growth factor (VEGF); and cytokines like transforming growth factor beta 1 (TGFβ 1), interleukin 1 alpha (IL -1α) and tumor necrosis factor alpha (TNF α).
[24],
[25],
[26]
Why do people go bald in Androgenetic Alopecia?
Many of the studies have accepted the role of androgens and the interplay between the dermal papillae and hair follicle as the critical processes involved in miniaturization of hair follicles.
The concentration of DHT along with 5 α reductase and androgen receptors are increased in the balding scalp.
[27],
[28] The other enzymes involved in conversion of weak androgens to potent androgens are 3 β hydroxysteroid dehydrogenase (3 β HSD) and 17 β hydroxysteroid dehydrogenase (17 β HSD) also show increased activity in Androgenetic Alopecia.
[29] The higher the concentration of androgen and androgen receptor, more the effect on expression of genes which control follicular cycling.
The signaling which follows at the dermal papillae and hair follicle interface in balding person results in premature termination of anagen associated with premature entry into catagen. Catagen occurs as a consequence of decreased expression of anagen maintaining factors, such as the growth factors- IGF-1, bFGF and VEGF. Also, an increased expression of cytokines (TGFβ 1, IL -1α and TNF α) promotes apoptosis.
[30] Recently, DKK-1 is found to be up regulated gene by DHT, resulting in inhibition of outer root sheath cells and triggering apoptosis.
[31]
Another recent advance is identification of the critical role of Wnt/β catenin signaling pathway in the maintenance of the DPC inductive properties required for hair follicle regeneration and growth of the hair shaft.
[32] The androgens and ligand activated AR can negatively influence the Wnt/β catenin signaling pathway.
[33] The androgens hamper the pathway by increasing the glycogen synthase kinase (GSK 3β) expression.
[34]
The exact roles and processes related to hair follicle stems cells in Androgenetic Alopecia are not clear. It is considered that while KRT15(hi) stem cells are maintained in bald scalp, there is a defect in conversion of hair follicle stem cells to CD200-rich and CD34-positive progenitor cells, both of which are needed to maintain proper follicular activity.
[35]
When do people go bald?
Androgenetic alopecia (Androgenetic Alopecia) is a multifactorial disorder caused by interactions between several genes and environmental factors.
Genes involved in Androgenetic Alopecia: A polygenic mode of inheritance is established due to the high prevalence and the wide range of expressed phenotypes in Androgenetic Alopecia. The genes influence predisposition through DNA sequence variations- single nucleotide polymorphisms, microsatellite repeats, insertion mutations, deletion mutations and copy number variations; or epigenetic modifications such as X chromosome inactivation, hypermethylation (switch off gene expression) or hypomethylation (switch on gene expression) of DNA in gene promoter regions.
[36],
[37]
The two major genetic risk loci are the X chromosome AR/EDA2R locus and the PAX1/FOX A2 locus on chromosome 20. Recent studies indicate HAD C9 locus on chromosome 7 as a new susceptibility locus.
[38],
[39],
[40],
[41]
The androgen receptor gene: The androgen receptor determines the sensitivity of cells to androgen. The AR gene regulates the potency of androgen available to the hair follicle. Of the many AR gene polymorphisms known, the
Stu 1 polymorphism has the most significant association with Androgenetic Alopecia.
[42]
Several other genes where associations could not be proved conclusively include 5α reductase, aromatase, estrogen receptor α and IGF-2 genes. The role of Y chromosome needs further comprehensive examination of the genome.
[43]
Hair follicle inflammation and environmental factors: The implication of follicular inflammation has been brought out by several studies. The process is slow, subtle and indolent unlike the inflammatory and destructive process in the classical scarring alopecia. Microbial toxins related to Propionibacterium sp., Staphylococcus sp., Malassezia sp., or Demodex could be involved in generation of inflammatory response.
[44] Alternatively, keratinocytes may respond to chemical stress from irritants in cosmetics and grooming agents, pollutants and actinic damage as in UV irradiation by producing radical oxygen species and nitric oxide.
[45]
