Once any steroid hormone is injected in the
body, it binds itself to the specific intracellular
receptor of the target cell once it diffuses
through the plasma membrane. In the same fashion,
androgens combine themselves with a cytosolic
(cytosol is the internal fluid of the cell
where a greater part of cell metabolism takes
place) or nuclear receptor protein once it
diffuses across the plasma membrane.
Technically, the androgen receptor is an
intracellular steroid receptor whose only
function is to bind testosterone and dihydrotestosterone.
Androgen receptors have two major forms A
and B which only differs in terms of their
molecular weight. This androgen-receptor complex
goes through a process of conformational changes
in the nucleus, which exposes the DNA-binding
sites, then binds itself to specific hormone
response elements in the DNA. This process
results in the dramatic change of the AR-androgen
comples (ARAC) which binds into the androgen-responsive
elements (ARE). The androgen-responsive elements
(ARE) are binding sited in the regions of
the DNA where ARAC could attach itself into
once it is transported to the nucleus. Many
of the bodily proteins contains ARE that are
encoded in their DNA which allows androgens
easier transcription modulation of the various
genes that it can activate or suppress.
Genes
The X chromosome has the gene for the androgen
receptor located at Xq11-12 and although ongoing
researches are suspecting that there are many
genes involved in the pattern baldness,
there is but one gene that has been properly
identified so far with the advances in the
research—the AR gene. This AR gene was
found out to be the one responsible in enabling
the body to make the androgen receptors, which
allow the body to respond to dihydrotestosterone
and other androgens.
AR Deficiency
The sensitivity of the cells to androgens
is attributed to the androgen receptors. There
were many genetic mutations that were noted
in the gene that encodes the AR in varieties
of diseases such as spinal and bulbar muscle
atrophy and prostate cancer (besides the androgen
insensitivity) – some of which are commonly
associated with functional changes in the
AR expression. When a particular androgen
receptor gene located in the X chromosome
mutates due in part by the absence of actively
functioning androgen receptors, a medical
complication called Androgen resistance syndrome
results. When this happens, a genetically
male fetus doesn’t undergo normal male
development but evolves into a phenotypically
female child instead.
It was noted that slight variations in the
AR gene causes an increased risk of pattern baldness; and expression of the AR is found
in numbers in a balding scalp. However, there
is no clear explanation how these genetic
changes could increase the risk of patterned
hair loss in both men and women. When slight
changes occur in the types of DNA building
blocks that make up the androgen receptor
gene, variations of the AR gene emerges. These
changes are frequent in men with premature
hair loss. An unknown mechanism triggers the
activation of the genes that are responsible
for the follicular miniaturization whenever
the DHT binds to androgen receptors in susceptible
hair follicles – a usual occurrence
in the case of bald men. Given this information,
it can be hypothesized that the androgen receptor
plays a key role in regulating the potency
of the available androgen to the hair follicle
and thus is an ideal candidate for the involvement
in the predisposition to pattern baldness.
Function
The regulation of gene transcription was
the first discovered mechanism of action for
androgen reactions. Recent studies had shown
that androgen-receptors can act independently
from their interaction with DNA – since
androgen receptors interact only with certain
signal transduction protein in the cytoplasm.
Signal transduction is the process by which
cells convert one kind of signal or stimulus
into another.
The direct interaction of androgen receptors
with testosterones occurs in some cell types
while in others, the testosterone is easily
converted by 5-alpha-reductase to dihydrotestosterone,
an even more potent agonist in activating
androgen receptor. In other words, DHT is
produced from testosterone. The order of affinity
of the androgen receptor binding in the various
steroid hormones is as follows: DHT> testosterone > estrogen > progesterone.
The receptor-DHT complex is more stable and
can persist longer in cells, making it roughly
3 to 4 times stronger agonist androgen-receptor
than testosterone. It has been found out that
the DHT is more effective compared to testosterone
in the promotion of up-regulation of the androgen
receptor. This phenomenon occurs because of
the augmentation of the rate of the synthesis
of receptors and the inhibition of receptor
turn over.
Interaction of DHT with AR and ARE
Evidence points out that DHT triggers the
androgen-mediated effects on the hair follicle
and the principal signal transduction cascade:
DHT-DHT/androgen receptor – ARE is
found to be similar in all hair follicles.
But study results of pattern baldness
have shown that DHT is responsible for the
growth of hair follicles, while terminal
hairs were found to have been converted
into thin vellus hair by miniaturization
in other areas. This leaves conclusive proof
that there are unknown mechanisms present
between hair follicle target-cells in androgen-dependent
sites and in androgen-independent growth
sites. While no definite explanation exists
so far, evidence points to the androgen
receptor or distinct ARE involvement in
the process.
Distribution of androgen Receptor in hair
follicles
Controversy surrounds the documented results
on the localization of androgen receptors,
and the conflicting results in the quantitative
concentrations of androgen receptors in bald
versus hairy scalps offer little to assuage
the curiosity.
It appears that the androgen receptor is
primarily located at the dermal papillae in
both anagen and telogen hairs. It is also
present in the dermal sheath cells, which
supports the concept that the possibility
of dermal sheath cells being able to replace
dermal papilla cells even in androgen-dependent
follicles is considerable. In frontal balding,
or Hamilton II to III androgenic alopecia,
Saway and Price were able to show a discrepancy
of 30% greater in the distribution of androgen
receptors in the frontal scalp hair follicles
compared to the occipital scalp hair follicles.
Randall and colleagues were able to show that
there is much higher amount of specific high-affinity,
low-capacity androgen receptor in the cultured
dermal papillae cells from androgen-dependent
sited compared to the non-balding scalp.