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Mechanism of action
Finasteride is a
competitive and specific inhibitor of Type II 5a-reductase,
an intracellular enzyme that converts the androgen
testosterone into DHT. Two distinct isozymes are found in
mice, rats, monkeys, and humans: Type I and II. Each of
these isozymes is differentially expressed in tissues and
developmental stages. In humans, Type I 5a-reductase is
predominant in the sebaceous glands of most regions of skin,
including scalp, and liver. Type I 5a-reductase is
responsible for approximately one-third of circulating DHT.
The Type II 5a-reductase isozyme is primarily found in
prostate, seminal vesicles, epididymides, and hair follicles
as well as liver, and is responsible for two-thirds of
circulating DHT.
In humans, the mechanism of
action of finasteride is based on its preferential
inhibition of the Type II isozyme. Using native tissues
(scalp and prostate), in vitro binding studies
examining the potential of finasteride to inhibit either
isozyme revealed a 100-fold selectivity for the human Type
II 5a-reductase over Type I isozyme (IC50=500 and
4.2 nM for Type I and II, respectively). For both isozymes,
the inhibition by finasteride is accompanied by reduction of
the inhibitor to dihydrofinasteride and adduct formation
with NADP+. The turnover for the enzyme complex is slow (t ½
approximately 30 days for the Type II enzyme complex and 14
days for the Type I complex).
Finasteride has no
affinity for the androgen receptor and has no androgenic,
antiandrogenic, estrogenic, antiestrogenic, or
progestational effects. Inhibition of Type II 5a-reductase
blocks the peripheral conversion of testosterone to DHT,
resulting in significant decreases in serum and tissue DHT
concentrations. Finasteride produces a rapid reduction in
serum DHT concentration, reaching 65% suppression within 24
hours of oral dosing with a 1-mg tablet. Mean circulating
levels of testosterone and estradiol were increased by
approximately 15% as compared to baseline, but these
remained within the physiologic range.
In men with male pattern hair
loss (androgenetic alopecia), the balding scalp contains
miniaturized hair follicles and increased amounts of DHT
compared with hairy scalp. Administration of finasteride
decreases scalp and serum DHT concentrations in these men.
The relative contributions of these reductions to the
treatment effect of finasteride have not been defined. By
this mechanism, finasteride appears to interrupt a key
factor in the development of androgenetic alopecia in those
patients genetically predisposed.
A 48-week, placebo-controlled
study designed to assess by phototrichogram the effect of
Propecia on total and actively growing (anagen) scalp
hairs in vertex baldness enrolled 212 men with androgenetic
alopecia. At baseline and 48 weeks, total and anagen hair
counts were obtained in a 1-cm2 target area of
the scalp. Men treated with Propecia showed increases
from baseline in total and anagen hair counts of 7 hairs and
18 hairs, respectively, whereas men treated with placebo had
decreases of 10 hairs and 9 hairs, respectively. These
changes in hair counts resulted in a between-group
difference of 17 hairs in total hair count (p<0.001) and 27
hairs in anagen hair count (p<0.001), and an improvement in
the proportion of anagen hairs from 62% at baseline to 68%
for men treated with Propecia. |
