development of human benign prostatic hyperplasia
(BPH) clearly requires a combination of testicular
androgens and the ageing process. Although the role
of androgens as the causative factor for human benign
prostatic hyperplasia is debated, they undoubtedly
play, at least, a permissive role. The principal
prostatic androgen is dihydrotestosterone. Although
not elevated in human benign prostatic hyperplasia,
dihydrotestosterone levels in the prostate remain
at a normal level with ageing, despite a decrease
in the plasma testosterone.
(DHT) is generated by a reduction in testosterone.
Two isoenzymes of 5alpha-reductase have been discovered.
Type 1 is present in most tissues in the body where
5alpha-reductase is expressed, and is the dominant
form in sebaceous glands. Type 2 5alpha-reductase
is the dominant isoenzyme in genital tissues, including
the prostate. Finasteride is a 5alpha-reductase
inhibitor that has been used to treat BPH and male-pattern
baldness. At doses used clinically, its major effect
is to suppress type 2 5alpha-reductase, because
it has a much lower affinity for the type 1 isoenzyme.
Finasteride suppresses DHT by about 70% in serum
and by as much as 85%-90% in the prostate. The remaining
DHT in the prostate is likely to be the result of
type 1 5alpha-reductase. The suppression of both
5alpha-reductase isoenzymes with GI198745 results
in greater and more consistent containment of serum
dihydrotestosterone than that observed with a selective
inhibitor of type 2 5alpha-reductase. Physiological
and clinical studies comparing dual 5alpha-reductase
inhibitors, such as GI198745, with selective type
2, such as finasteride, will be needed to determine
the clinical relevance of type 1 5alpha-reductase
within the prostate. There have been two large,
international multicentre, phase III trials published
documenting the safety and efficacy of finasteride
in treating human benign prostatic hyperplasia.
Combining these two studies, randomised, controlled
data are available for 12 months.
extension of these data from a subset of patients,
who elected to continue on the drug for 3, 4 and
5 years, are also available. Long-term medical therapy
with finasteride can reduce clinically significant
endpoints, such as acute urinary retention or surgery.
According to the meta-analysis of six randomised,
clinical trials with finasteride, finasteride is
most effective in men with large prostates. A more
effective dual inhibitor of type 1 and 2 human 5alpha-reductase
may lower circulating dihydrotestosterone to a greater
extent than finasteride and show advantages in treating
human benign prostatic hyperplasia and other disease
states that depend on dihydrotestosterone. A clinical
evaluation of potent dual 5alpha-reductase inhibitors
may help to define the relative roles of human type
1 and 2 5alpha-reductase in the pathophysiology
of benign prostatic hyperplasia and other androgen-dependent