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 ( t1/2 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.
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.
Finasteride had no effect on circulating levels of cortisol,
thyroid-stimulating hormone, or thyroxine, nor did it affect
the plasma lipid profile ( e.g., total cholesterol, low-density
lipoproteins, high-density lipoproteins and triglycerides
) or bone mineral density. In studies with finasteride,
no clinically meaningful changes in luteinizing hormone
( LH ) or follicle-stimulating hormone ( FSH ) were detected.
In healthy volunteers, treatment with finasteride did not
alter the response of LH and FSH to gonadotropin-releasing
hormone, indicating that the hypothalamic-pituitary-testicular
axis was not affected. Mean circulating levels of testosterone
and estradiol were increased by approximately 15% as compared
to baseline in the first year of treatment, but these levels
were within the physiologic range.
