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Pathology
To look under the skin and see what happens to the hair follicles
in androgenetic alopecia a punch biopsy is taken. Simply, a small
metal tube with a razor sharp edge usually about 4mm in diameter
is pushed into the skin at the same angle as the hair follicles.
The tube acts like a paper punch and cuts a circular piece of
skin out of the scalp. This sample is then sent for processing
in a histology laboratory and then passed to a pathologist for
analysis under a microscope.
The gradual changes that occur in the androgenetic alopecia
affected scalp skin is the same whether describing male of female
baldness. Androgenetic alopecia does not develop in all hair follicles
at the same time. Some are more quickly affected than others.
When looking at a punch biopsy under the microscope neighboring
hair follicles can be seen to be variably affected. Some will
be normal healthy terminal hairs with an average diameter of 0.06mm,
others will be miniaturized vellus hair follicles with an average
diameter of 0.03mm. So, one parameter of androgenetic alopecia
is a decrease in the density of terminal hairs and an increase
in the vellus hair count. Hairs in an intermediate state between
terminal and vellus hairs will also be observed.
Over time the terminal scalp hair follicles undergo progressively
shorter and shorter cycles involving reduced anagen growth periods.
This applies regardless of whether the hair follicles are terminal,
intermediate, or vellus hairs. Although periods of anagen are
reduced catagen and telogen time periods remain the same. The
net effect is that androgenetic alopecia is characterized by a
gradual increase in the number of resting telogen hair follicles
present at any one time. In unaffected scalp the percentage of
hair follicles in telogen is up to 10%. In the early stages of
androgenetic alopecia affected scalp the number of telogen stage
hair follicles can be up to 20% of the total. As androgenetic
alopecia progresses the total number of hair follicles can be
reduced as the hair follicles are irreversibly destroyed.
In androgenetic alopecia the terminal hair follicles reduce
size both in length and diameter. The hair bulb moves upwards
in the dermis yielding a small vellus hair follicle. These vellus
hair follicles can be affected by fibrosis. Beneath the miniaturized
vellus hair follicle a fibrous tract, known as a streamer or follicular
stela, can be observed marking the terminal hair follicle bulb’s
original position to the base of the current vellus hair dermal
papilla. In many cases of androgenetic alopecia an inflammatory
infiltrate can be seen around the affected hair follicles especially
the upper hair follicles. Normal unaffected scalp hair follicles
can also have mild inflammation but the inflammation in androgenetic
alopecia is often much more intense with many more cells involved.
How
do androgens cause baldness?
The answer to this is not straight forward. Androgens are steroid
hormones that have a profound influence on a range of biological
mechanisms. Several types of androgens can affect hair follicles
and different types of hair follicles in different regions of skin
respond differently to the same androgen.
We have several factors to consider when explaining androgenetic
alopecia
- 1) Concentration of low potency androgens in the blood stream
- 2) Concentration of high potency androgens in the blood stream
- 3) Concentration of enzymes in the hair follicles that can convert
low potency hormones to high potency hormones
- 4) Hair follicles that are androgen independent
- 5) Hair follicles that are androgen dependant
- 6) Androgen dependant hair follicles that respond with proliferation
- 7) Androgen dependant hair follicles that respond with miniaturization
and inactivity
- 8) Number of androgen receptors in androgen dependant hair follicles
- 9) Sensitivity of androgen receptors in androgen dependant hair
follicles
- 10) Nature of factors induced by androgen receptor binding
- 11) Concentration of factors induced by androgen receptor binding
- 12) The rate of androgen metabolism/breakdown and removal from
the system
With so many variables the development of androgenetic alopecia
in any one individual can be difficult to predict.
There are two key types of androgen hormone that we need to consider
when explaining baldness, testosterone and dihydrotestosterone (DHT).
Actually, dihydrotestosterone is a derivative of testosterone. An
enzyme called 5 alpha reductase converts the relatively inactive
testosterone to the very potent dihydrotestosterone. 5 alpha reductase
is a key enzyme found in hair follicles especially the dermal papilla.
So, less potent hormones can be converted to more potent acting
androgen subtypes by enzymes in the skin and hair follicles.
Once dihydrotestosterone is formed by the enzyme action the potent
androgen has a powerful ability to bind to any androgen receptors
in hair follicles. Although dihydrotestosterone is the most potent
androgen that affects hair follicles other androgens can also have
a more limited effect. Plain old testosterone can act on hair follicles
and adrenal androgens might also have a weak effect. Binding of
the androgen receptors triggers the hair follicle cells and transcription
proteins alter the cells' gene activity. The change in gene activity
reduces the cells’ activity and slows down proliferation and
hair growth on the scalp.
Differences
in mechanisms of androgenetic alopecia for men and women
The steroidal interconversion system in our bodies is very complex.
There are a wide range of androgen subtypes interconverted by enzymes
in a cascade of events. Some androgen subtypes can be converted
other androgen subtypes and back again. The same can be said of
the estrogens. On top of this androgens can be metabolized to estrogens
by the Cytochrome P-450-aromatase enzyme. Under certain circumstances
aromatase can apparently convert estrogens back to androgens although
this is a much less frequent occurrence than conversion of androgens
to estrogens. These interconversions of hormones with different
levels of potency and influence on hair follicles are important
in defining the nature of androgenetic alopecia for men and women.
From the complex interactions of androgens and estrogens the basic
message for hair biologists is that in men testosterone is the major
precursor of dihydrotestosterone that is converted by the alpha
5 reductase type I and II enzymes. In women dehydroepiandrosterone
(DHEA) from the adrenal glands is a key precursor of dihydrotestosterone
and requires conversion by both alpha 5 reductase enzymes and hydroxysteroid
hydrogenase isomerase enzyme.
In male androgenetic alopecia hair loss is dependant on an interplay
between androgen receptors in the hair follicles, 5 alpha reductase
type I and II converting enzyme concentration and local concentrations
of dihyrotestosterone around hair follicles. In women the presumption
is that additional factors come into play such as the concentration
of Cytochrome P-450-aromatase near hair follicles that will metabolize
androgens to estrogens, and the ratio of androgens to estrogens
as estrogens will antagonize the effects of androgens.
Drs Price and Sawaya have conducted several analyses to compare
the nature of female androgenetic alopecia to male alopecia. They
have identified differing concentrations of androgen metabolizing
enzymes and androgen receptors in hair follicles from women compared
to men and they hypothesize these differences are what makes the
pattern of female hair loss different from that of male pattern
baldness. They found that Cytochrome P-450-aromatase content was
up to six times more concentrated in women's frontal hair follicles
compared to men's frontal hair follicles. They particularly note
that the aromatase enzyme is present in greater concentrations at
the back of the scalp and less so at the front in women whereas
men have only small amounts of aromatase present in any region of
their scalp. Women had around 3 times less alpha-5-reductase type
I or type II enzyme in their frontal hair follicles compared to
men. Conversely, androgen receptor content in frontal hair follicles
from men are 40% higher than for hair follicles from women (Sawaya
1997). These differences between men and women most likely account
for the overt clinical differences in patterns of hair loss.
Androgenetic alopecia in women can be promoted by hormone fluctuations.
The steroidal interconversion system can act on available hormones
particularly those involved in pregnancy or from using pregnancy
equivalent drugs such as contraceptives. Sudden hormonal changes
when starting or stopping contraceptives or at the beginning or
end of pregnancy and at the start of menopause, may promote androgenetic
alopecia onset.
Is
androgenetic alopecia exclusively inherited from the maternal family
tree?
A popular explanation for the genetic inheritance of androgenetic
alopecia is that women are carriers of the genes that are then expressed
in their male offspring. In other words the genes for baldness are
exclusively supplied by the mother. However, in practice this does
not seem to be the case. Genetic analysis of androgenetic alopecia
gene candidates shows that pattern baldness is autosomal dominant.
In other words, you can inherit baldness genes from both your mother
and your father.
Androgenetic alopecia is believed to be a polygenic condition
with susceptibility genes on several non-sex chromosomes. The inheritance
of alopecia genes is much more complex than was originally thought.
The genes that effect baldness most likely include those involved
in testosterone synthesis, 5 alpha reductase production, and androgen
hormone receptors in hair follicles. However, so far no significant
gene polymorphisms have been identified that may be involved in
baldness.
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