Androgens in Health and Disease.pdf - E Library

82 Sutton, Amory, and Clark
Finasteride has also been studied as therapy for men already diagnosed with CaP. In
a 12-wk study of 28 asymptomatic men with metastatic CaP (Stage D), finasteride 10 mg
daily had no effect on prostatic acid phosphatase, serum testosterone, prostate volume,
or lesions on bone scan, although PSA levels were significantly lower in men treated with
finasteride (70). In a study of men with elevated PSAs (0.6–10.0 ng/mL) and no evidence
of recurrent CaP following radical prostatectomy, 10 mg finasteride daily for 24 mo delayed
progressive increases in PSA by an average of 14 mo and did not appear to influence
response to subsequent androgen-deprivation therapy in those men in whom recurrent CaP
was ultimately diagnosed (71). Recurrent disease was diagnosed in 5/41 men (12%) treated
with finasteride and 8/43 men (19%) treated with placebo; although this difference was not
statistically significant, it raises the possibility that finasteride treatment reduces or delays
recurrence (71). Finasteride has also been proposed as potentially effective “maintenance”
therapy for men with CaP who have favorable PSA responses following androgen blockade
with nonsteroidal antiandrogens and/or GnRH agonists (29).
Finasteride is a selective 5α-reductase type II antagonist and incompletely blocks the
intraprostatic conversion of T to DHT (approx 80% reduction). It may be that residual
intraprostatic DHT is sufficient for the development or progression of prostate cancer.
It has also been observed that 5α-reductase type I is upregulated in prostate cancer cell
lines in vitro, as well as in many prostate cancer ex vivo samples (72,73). Although it may
well be that the upregulation of 5α-reductase type I is an artifact of in vitro culture (74)
or may be a consequence of dedifferentiation in vivo, it may also be true that CaP
develops in a milieu where 5α-reductase type I is the dominant isozyme. Finasteride, a
selective inhibitor of 5α-reductase type II, would not be expected to prevent the development
of CaP if this were the case (75). Inhibitors of both 5α-reductase isozymes, such
as dutasteride might be better candidates for hormonal chemoprevention of CaP (29,76).
Interestingly, results from the phase III clinical trials with dutasteride show a reduction
in diagnosed cancer incidence in the treated group compared to placebo, 1.1% (24/2167
patients) on dutasteride vs 1.9% (42/2158 patients) on placebo (60). It may also be true
that T, not DHT, is the androgen necessary and sufficient for the pathogenesis of CaP.
Testosterone levels are actually increased during treatment with finasteride (31). It may
be necessary to reduce both T and DHT levels in order to prevent CaP or prevent the
progression of PIN to CaP.
Androgenic Alopecia and Hirsutism
Finasteride is also FDA-approved for the treatment of male pattern baldness, or
androgenic alopecia (AGA). Male pattern baldness results from a shortening of the
anagen (growth) phase and prolonging the telogen (rest) phase of hair follicles, resulting
in progressively finer, shorter hair (77). AGA occurs in 23–87% of adult males and may
occur in women as well (77). AGA does not occur in the absence of androgens (78).
The rationale for the use of a 5α-reductase inhibitor in the treatment of AGA again
stems from observations of cohorts of patients with familial male pseudohermaphroditism
as a result of 5α-reductase type II deficiency, in which AGA does not develop (25).
Furthermore, concentrations of DHT in the sebum are higher in bald areas of the human
scalp than in areas with hair (79). Both type I and type II 5α-reductase isozymes are
found in the male scalp, with the type II isozyme present in hair bulbs and the type I
enzyme present in sebaceous glands (80). The distribution of 5α-reductase in the scalp
parallels the distribution of DHT, with highest concentrations found in the vertex and