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Androgen-dependent Hair
Numerous factors affect the number and activity of androgen receptors
in dermal papilla cells. Retinoic acid (vitamin A derivative), if used
for a long time, may reduce the number of androgen receptors by 30 - 40
percent.[29] Vitamin B6 reduces by 35-40% the extent of protein
synthesis observed after androgen receptor activation.[30] A
polypeptide with molecular weight of 60 kDa, analogous to an
intracellular calcium-binding protein called calreticulin, prevents
binding of the androgen-receptor complex to DNA and also results in the
production of calreticulin.[31
Androgens have diverse effects on hair in different body regions.[22]
Effects vary from essentially nonexistent (e.g. on eye-lashes), weak
(on temporal and suboccipital region hair), moderate (on extremity
hair), or strong (on facial, parietal region, pubic, chest, and
axillary hair). Androgens bind to receptors both in the cytoplasm and
nuclei of dermal papilla cells and some cells of the sheaths of the
follicle, but only if the hair is in anagen or telogen.[23,24] Two
molecular forms of androgen receptors have been proposed: active
(protein-monomer, 62 kDa) and inactive (protein-tetramer, with four
subunits, total molecular weight 252 kDa). The monomer form has much
greater affinity for androgens (dissociation constant for
dihydrotestosterone is 2.9 nM). Four monomer molecules aggregate to
form a tetramer in a reversible reaction.[23] Necessary factors are
glutathione and the enzyme, endogenous disulfide converting factor. The
complex of androgen hormone-receptor moves to the cell nucleus and
there enables expression of genes coding cytokines. Cells of the dermal
papilla synthesize and secrete cytokines which control growth and
differentiation of hair matrix cells.[25,26,27,28] In most hair the
released cytokines stimulate matrix cell division and differentiation,
however for hair of the parietal region the cytokines act as
inhibitors, leading to follicle atrophy.
Among all androgens, dermal papilla cells are most affected by 5- -
dihydrotestosterone (5 -DHT). It is synthesized in these cells from
testosterone under catalytic action of the enzyme 5- -reductase.[32]
This enzyme exists in two forms (isoenzymes) - type I and type II
.[33,34] 5- -dihydrotestosterone is further reduced to 3- -
androstanediol which, after conjugation with glucuronic acid, is
excreted in urine. Plasma and urine levels of 3- -androstanediol
glucuronide are the most precise clinical indicators of the extent of
testosterone transformation to 5- -DHT).[35] They are elevated in
hirsute women.
Growth of androgen-dependent hairs can be influenced in several ways:
(a) by decreasing androgen production, (b) by blocking testosterone
transformation to 5- -DHT or (c) by blocking androgen receptors.
Androgen production can be decreased either surgically (removal of
hormone-producing ovarian or adrenal tumor) or with drugs. If increased
production of androgens is the consequence of adrenal cortex
hyperplasia, it can be suppressed with cortisone. Exogenous cortisone
will inhibit release of ACTH from the hypophysis, and this in turn will
decrease hyperplasia. If increased androgen production is caused by
polycystic ovarian dystrophy, it can be reduced by inhibition of
hypophyseal release of gonadotropins. Continuous administration of
gonadorelin analogs (leuprolide, goserelin, decapeptyl, etc.) is a very
efficient tool for achieving this goal. However, administration of
these drugs is accompanied by significant adverse effects that result
from decreased estrogen and progesterone production. Menstrual
irregularities, flushes and osteoporosis are commonly observed (36).
These adverse effects can be reduced by simultaneous administration of
estrogen (during the first 21 days of the menstrual cycle) and
progesterone (from 12th to 21st days of the cycle).
Transformation of testosterone to 5- -DHT can successfully be
interrupted with inhibitors of 5- -reductase. One of them, finasteride,
is already used clinically with significant efficacy [37] without
disturbance of sex hormone plasma levels. Finasteride only inhibits
type II 5- -reductase.[37] There are other 5- -reductase blockers (so-
called azasteroids), that have a steroid nucleus with an attached 4-
methyl-4-azo moiety and a long hydrophobic side chain on C-17. The most
efficient among them is 17 -N,N-diethylcarbamyl-4-methyl-4-aza-5 -
androstan-3-one, which has a greater effect on in-vitro hair follicle
cultures than finasteride.[38]
One way to suppress the growth of androgen-dependent hairs is by the
blockade of androgen receptors. The competitive androgen receptor
blocker flutamide has already been approved for human use. Women with
idiopathic hirsutism taking flutamide experienced a 30% reduction of
hair diameter without disturbance of plasma levels of gonadotropins,
testosterone, androstenedione or dehydroepiandrostenedione.[39]
Treatment should consist of daily administration of 375 mg for several
months.[40] Compared to spironolactone (a diuretic with androgen
receptor blocking activity), flutamide is about 3 times more effective
[41,42] with less adverse effects (menstrual irregularities).
Several blockers of androgen receptors with non-steroid chemical
structure were synthesized recently. They are N-substituted
arylthiohydantoins: RU 59063, RU 56187 and RU 58841.[43,44] These are
very potent substances. Their affinity for androgen receptors is three
times higher than the affinity of testosterone. One of them, RU 58841,
is active when applied locally, which is of great benefit considering
the significant adverse effects observed after systemic administration.
One of the imidazole antimycotics, ketoconazole, is an inhibitor of
androgen biosynthesis and also an androgen receptor blocker, however
its affinity for androgen receptors is low. Systemic administration of
ketoconazole for the treatment of hirsutism requires high doses and is
associated with a high incidence of adverse effects.[45] "
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