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5a-reductase inhibitors in benign prostatic
hyperplasia and prostate cancer
risk reduction
Roger S. Rittmaster
*
MD
Group Director
Urology Clinical Development and Medical Affairs, GlaxoSmithKline, 5 Moore Drive,
PO Box 13398, Research Triangle Park, North Carolina 27709, USA
Androgens play an essential role in prostatic development and function, but are also involved in
prostate disease pathogenesis. The primary prostatic androgen, dihydrotestosterone (DHT), is
synthesized from testosterone by 5a-reductase types 1 and 2. Inhibition of the 5a-reductase
isoenzymes therefore has potential therapeutic benefit in prostate disease. The two currently
approved 5a-reductase inhibitors (5ARIs), finasteride and dutasteride, have demonstrated
long-term efficacy and safety in the treatment of benign prostatic hyperplasia. Finasteride,
a type-2 5ARI, has also been studied for its ability to reduce the incidence of biopsy-detectable
prostate cancer in the Prostate Cancer Prevention Trial. Treatment with dutasteride, a dual
5ARI, has been shown to result in a greater degree and consistency of DHT suppression
compared with finasteride. Two large-scale studies of dutasteride are currently investigating
the role of near-maximal DHT suppression in the settings of prostate cancer risk reduction
and expectant management of localized prostate cancer.
Key words: 5a-reductase; 5a-reductase inhibitor; androgen; Avodart; benign prostatic hyper-
plasia; dihydrotestosterone; dutasteride; finasteride; prostate; prostate cancer.
Androgens play an essential role in prostatic development, growth and function. Dur-
ing puberty, increasing androgen levels result in extensive morphological changes to
the gland, giving rise to the complex glandular architecture seen in the adult. Mainte-
nance of the adult prostate is under continuous androgenic control, and androgen dep-
rivation as a result of castration causes apoptosis of prostatic epithelium and prostatic
involution. However, later in life androgens play a significant role in prostate disease
pathogenesis, particularly benign prostatic hyperplasia (BPH) and prostate cancer.
* Tel.: þ1 919 483 1287; Fax: þ1 919 315 3401.
E-mail address: roger.s.rittmaster@gsk.com
1521-690X/$ - see front matter ª 2008 Elsevier Ltd. All rights reserved.
Best Practice & Research Clinical Endocrinology & Metabolism
Vol. 22, No. 2, pp. 389–402, 2008
doi:10.1016/j.beem.2008.01.016
available online at http://www.sciencedirect.com
Both conditions are progressive, with a long natural history, and are common in ageing
men. BPH progression is characterized by an increase in prostate volume, decrease in
peak urinary flow rate (Qmax), and worsening of lower urinary tract symptoms
(LUTS). This may lead eventually to complications such as acute urinary retention
(AUR) and the need for BPH-related surgery. Prostate cancer development is also
widely believed to be a progressive process occurring over many decades. Damage
to prostate epithelium caused by infection, inflammation and carcinogen exposure
leads to the formation of proliferative inflammatory atrophy (PIA), a prostate cancer
precursor lesion.
1
Subsequent somatic genome alterations may then drive progression
to prostatic intraepithelial neoplasia (PIN) and localized prostate cancer, and later de-
velopment of metastatic disease.
The role of androgens in prostate disease was suggested over a century ago, when
‘testicular factors’ were recognized in the pathogenesis of prostatic enlargement
through the practice of surgical castration. Further evidence came from the observa-
tion that males who have been castrated prepubertally – and as a consequence have
very low levels of circulating testosterone – do not develop BPH. The first major
advancement in our understanding of the pivotal role of androgens in prostate cancer
came in the 1940s when castration was demonstrated to have a clinical benefit in men
with metastatic prostate cancer.
2
The biological basis of this outcome is the androgen-
responsiveness of prostate cancer cells
3
, a feature that is now well understood
4
and
which is shared with their prostatic epithelial precursors.
5
In the normal prostate,
a complex, androgen-dependent signalling relationship exists to balance proliferation
and apoptosis so that no net growth occurs.
6
In prostate disease, this homeostatic
state becomes disrupted in favour of cell proliferation, leading to benign or malignant
growth.
Our understanding of the pivotal role of androgens in prostate disease led to the
hypothesis that interventions to reduce the androgen drive in the prostate may
have the potential to reduce the risk of disease development, to slow or even prevent
disease progression, and to treat existing disease. However, androgen-ablative therapy
is associated with significant adverse events such as sexual dysfunction, depression,
osteoporosis, anaemia and muscle weakness. While these events may be considered
acceptable in the context of treatment of aggressive prostate cancer, they would be
considered too severe for the treatment of BPH, and certainly inappropriate for
preventive approaches. What was needed was an alternative approach to reduce an-
drogen drive to the prostate.
The discovery that dihydrotestosterone (DHT), and not testosterone, is the pri-
mary androgen in the prostate opened new possibilities for manipulation of the an-
drogen axis. Within the prostate, both testosterone and DHT bind to the androgen
receptor and activate the protein in the same manner (Figure 1).
7
Although the two
hormones have similar association rates, DHT dissociates more slowly from the an-
drogen receptor and induces a receptor conformation more resistant to degrada-
tion than testosterone.
8
Thus, under steady-state conditions, most androgen
receptors in the prostate are occupied by DHT rather than testosterone.
7
DHT
is also intrinsically about twice as potent as testosterone at stimulating prostate
growth.
9
DHT is synthesized from testosterone under the catalysis of two isoenzymes of 5a-
reductase, types 1 and 2. Given the higher potency and avidity of DHT versus testos-
terone at the androgen receptor, a major role of 5a-reductase is therefore to enhance
the androgenic signal in tissues with a high concentration of these enzymes, such as the
prostate. The 5a-reductase isoenzymes therefore also act to maintain normal prostate
390 R. S. Rittmaster
function even at low circulating testosterone levels.
9
Mutations in type-2 5a-reductase
cause male pseudohermaphroditism
10
in which affected males have elevated plasma
testosterone levels with decreased DHT levels. Ambiguous external genitalia are pres-
ent at birth, and although virilization occurs at puberty, the prostate remains small. Of
particular note is that men with type-2 5a-reductase gene mutations do not develop
BPH or prostate cancer.
10
Inhibition of 5a-reductase isoenzymes, it was hypothesized, could result in a dra-
matic reduction in androgen drive to the prostate, but with concurrent maintenance
of testosterone levels, important in reducing the adverse effects associated with an-
drogen-ablative therapy. Such an approach held the promise of better therapies for
prostate cancer, the possibility of medical therapy to impact the underlying disease
in BPH, and the chance to consider the role of 5a-reductase inhibition in disease pre-
vention. Finasteride, a type-2 5a-reductase inhibitor (5ARI) was the first to be ap-
proved by the US Food and Drug Administration (FDA) for the treatment of
symptomatic BPH in 1992. Subsequently, a targeted drug discovery programme led
to the clinical development of dutasteride, a dual 5ARI, which was approved for the
same indication in 2002. This chapter reviews our understanding of the 5a-reductase
isoenzymes, the endocrine, clinical and histological effects of 5ARIs, and the evidence
supporting their use in the treatment of BPH and reducing the risk of prostate cancer
development.
Figure 1. Mediation of dihydrotestosterone (DHT) effects within the prostate. Following the conversion of
testosterone to DHT by the 5a-reductase isoenzymes, DHT binds to the androgen receptor, causing disso-
ciation of heat-shock proteins and allowing translocation of the androgen receptor into the nucleus. Subse-
quent binding to androgen-response elements (AREs) in the presence of coactivator proteins enables
transcriptional activation of target genes.
5a-reductase inhibitors in prostate disease 391
THE 5a-reductase isoenzymes
Type-2 5a-reductase is found predominantly in the prostate and other genital tissues,
whereas type-1 is found throughout the body wherever 5a-reductase is expressed,
including the skin, liver and prostate. Studies of male pseudohermaphrodites have
provided insight into the role of type-2 5a-reductase in normal human physiology;
corresponding models of type-1 deficiency have not yet been identified, and so its
role remains to be fully elucidated. Unexpectedly, male mice with type-1 and -2
knock-outs have normal virilization in utero and are fertile, although their prostate
glands remain small throughout life.
11
Therefore, these models have not proved help-
ful in defining the exact role of the 5a-reductase isoenzymes in men. In humans, ex-
pression of both isoenzymes is enhanced in BPH tissue compared with normal
prostate, with higher expression of type-2 than type-1 5a-reductase in hyperplastic
tissue.
12
However, in situ hybridization and immunostaining studies have shown that
expression of type 1 is enhanced during the development of prostate cancer, while
that of type 2 is decreased or unchanged (Figure 2).
12,13
Most recently, it has been
shown that the levels of type-1 and type-2 5a-reductase are increased in localized
high-grade compared with low-grade prostate cancer.
14
Development of prostate dis-
ease therefore appears to be associated with increased expression of both 5a-reduc-
tase isoenzymes, while over-expression of type-1 may be of particular importance in
Figure 2. Relative immunostaining of 5a-reductase types 1 and 2 in prostatic intraepithelial neoplasia (PIN),
localized prostate cancer, recurrent prostate cancer and prostate cancer metastases, compared with staining
in BPH tissue.
13
Reprinted from Thomas et al (2005, Prostate 63: 231–239) with permission of Wiley-Liss,
Inc., a subsidiary of John Wiley & Sons, Inc.
392 R. S. Rittmaster
the development and progression of prostate cancer. Therefore, one may hypothesize
that inhibition of both isoenzymes might exhibit enhanced prostate cancer risk
reduction.
EFFECTS OF 5ARIS ON SEX HORMONE LEVELS
The major differences between the two clinically available 5ARIs, finasteride and du-
tasteride, are shown in Table 1. Of particular note is that dutasteride is 45-fold
more potent in inhibiting type-1 and two-fold more potent in inhibiting type-2 5a-
reductase than finasteride.
15
In a phase-II dose-ranging study, the mean decrease in
serum DHTat week 24 was 94.7% for patients who received 0.5 mg dutasteride com-
pared with 70.8% for patients who received 5.0 mg finasteride (P <0.001).
16
Further,
DHT suppression of 90% was noted in 85.4% of patients who received dutasteride
compared with 2.2% of those who received finasteride.
17
Intraprostatic DHT suppres-
sion of 68–86% has been reported for finasteride.
15
In contrast, daily dutasteride
0.5 mg resulted in a 94% reduction in intraprostatic DHT compared with placebo after
three months
18
, while a 3.5-mg daily dose suppressed intraprostatic DHT by 99% after
4 months.
19
Table 1. Comparison of finasteride and dutasteride.
Finasteride Dutasteride
Molecular
class
4-Azasteroid 4-Azasteroid
Empirical
formula
C
23
H
36
N
2
O
2
C
27
H
30
F
6
N
2
O
2
Structural
formula
Molecular
weight
372.55 528.5
Half-life 6 hours (range 3e16) w5 weeks
5a-
reductase
inhibition
profile
Type 2 Type 1 and type 2
Clinical
dosage
5.0 mg/day 0.5 mg/day
DHT
suppression
w70% w90%
5a-reductase inhibitors in prostate disease 393
As would be expected from observations in men with certain mutations in type-2
5a-reductase, DHT suppression through 5a-reductase inhibition is accompanied by
a reciprocal increase in testosterone levels. However, in most studies, intraprostatic
testosterone did not increase as much as DHT decreased, and so the total intrapro-
static androgen concentration was decreased. Taking into account the lower potency
of testosterone compared with DHT, 5ARI treatment therefore significantly reduced
the total androgen effect within the prostate.
In order to determine whether DHT suppression causes an increase in gonadotro-
pin secretion, the effects of 5ARI therapy on serum gonadotropins have been investi-
gated in a small, placebo-controlled study.
20
After 4 weeks of finasteride treatment, no
changes in basal or gonadotropin-releasing-hormone-stimulated luteinizing hormone
or follicle-stimulating hormone levels were seen, despite marked reductions in serum
DHT. A second study demonstrated that finasteride had no effect on serum oestradiol
levels.
21
These findings provided reassurance that 5ARI therapy results in minimal or
no changes in the circulating levels of gonadotropins or oestradiol.
HISTOLOGICAL EFFECTS OF 5ARIS
The effects of 5ARIs on BPH tissue at a cellular and glandular level have been examined
in a number of animal and human studies. Finasteride has been shown to cause invo-
lution of rat ventral prostate through a reduction in ductal luminal fluid and apoptotic
cell loss.
22
However, the process occurred more slowly and to a lesser extent than
with castration. Examination of normal and hyperplastic human prostates have shown
that finasteride treatment results in atrophy and involution, smaller nuclei and nucleoli,
increased apoptosis, decreased microvessel density, and no increase in cell prolifera-
tion.
23
There is evidence that these effects on the prostate are mediated through a re-
duction in epithelial, but not stromal, volume, due to both atrophy and apoptosis.
24
At
a glandular level, 5ARI-induced reductions in epithelial volume result in prostate
shrinkage, with volume reductions occurring equally in the transitional and peripheral
zones.
25
Similar histological effects of the 5ARIs have also been demonstrated in prostate
cancer cells. For example, in a study of five prostate cancer patients treated with finas-
teride, atrophic effects were seen that were similar to, but less prominent than, those of
androgen ablation in 113 controls.
26
Although androgen-deprivation changes were no-
ticeable in Gleason grade-2 or -3 tumours in the finasteride group, they were minimal in
grade-4 tumours. Conversely, a later needle biopsy study found no histopathological
differences between finasteride-treated and untreated cases, including Gleason score,
atrophic changes in cancer cells and presence of prominent nucleoli.
27
However, 6–10
weeks of pre-treatment with dutasteride 5 mg was found to cause increased apoptosis
and a trend towards decreased microvessel density in 46 men undergoing radical pros-
tatectomy when compared with placebo.
28
Tumour volume was significantly lower in
dutasteride-treated men compared with placebo, the percentage of atrophic epithelium
was increased and the stromal/gland ratio was doubled.
29
However, in a longer (4-
month) study, dutasteride did not cause an increase in apoptosis or a decrease in pro-
liferation or microvessel density.
19
One explanation is that markers of proliferation and
apoptosis change within days of androgen deprivation in prostate cancer and then
return towards baseline rapidly thereafter.
30
Overall it appears that 5ARI treatment re-
sults in similar but less marked changes compared with androgen ablation.
Strong evidence to support the relevance of type-1 5a-reductase in prostate
cancer was recently provided in a preclinical study in which rats bearing the Dunning
394 R. S. Rittmaster
R-3327H xenograft were randomized to varying doses of daily finasteride or dutas-
teride for 55 days.
31
Treatment with finasteride significantly decreased normal ventral
prostate weight and DHT concentration in these animals, but had no significant effect
on H tumour growth or DHT content. In contrast, dutasteride reduced both ventral
prostate and H tumour DHT concentration and weight. This finding can be explained
by the fact that whereas normal prostate expresses a preponderance of type-2 5a-re-
ductase, the balance of 5a-reductase isoenzyme expression shifts to type 1 in H tu-
mours. Only the dual inhibitory effect of dutasteride was therefore able to inhibit
tumour growth in this animal model. This finding is consistent with previous clinical
trials with finasteride that demonstrated limited success to in the treatment of met-
astatic prostate cancer.
32,33
Collectively, these data lend support the hypothesis that
dual 5a-reductase inhibition could slow the progression, or even cause regression, of
early prostate cancer.
5ARIS IN THE TREATMENT OF BPH
A large body of data from randomized clinical trials has demonstrated the efficacy
and safety of 5ARIs in the treatment of BPH. Two phase-III trials of finasteride
showed significant benefit in terms of urinary symptoms, prostate volume and
Qmax versus placebo at 1 year in men with mild to severe symptomatic BPH
34,35
,
while the Proscar Long-term Efficacy and Safety Study (PLESS) demonstrated a signif-
icant reduction in the risk of AUR and the need for BPH-related surgery with finas-
teride after 4 years.
36
Open-label extensions of these studies showed that these
beneficial effects were sustained with longer follow-up.
37,38
Similar outcomes were
seen at 2 years for dutasteride in three large-scale, randomized, controlled trials
of men with moderate to severe symptomatic BPH.
39
A 2-year open-label extension
of these studies demonstrated continued prostate volume decreases and further im-
provements in symptoms and Qmax for patients who received dutasteride through-
out the study.
40
For all efficacy parameters, the magnitude of benefit was significantly
greater in patients who received 4 years of dutasteride therapy compared with those
originally randomized to placebo and switched to dutasteride at month 24. This find-
ing indicates that longer duration of therapy with dutasteride appears to result in
greater clinical benefits.
To date, no large-scale, long-term, head-to-head studies between finasteride and
dutasteride have been conducted. Limited data from a 1-year study showed no statis-
tical difference between finasteride and dutasteride in terms of mean changes in pros-
tate volume, American Urological Association-Symptom Index (AUA-SI) score or
Qmax.
41
At month 48 in the dutasteride phase-III studies, AUA-SI scores had de-
creased 6.5 points from baseline (after the placebo run-in).
40
This is greater than
was seen in similar finasteride studies; however, the patient populations were different,
making direct comparisons difficult. All dutasteride BPH studies have been conducted
in patients with enlarged prostates (30 cc), whereas prostate volume was not an en-
try criterion for studies with finasteride.
More recently, the benefits of combining a 5ARI with an a-blocker have been ex-
amined in men with symptomatic BPH. The rationale behind this was based on the
fact that, at a mechanistic level, their modes of action can be considered to be com-
plementary. The Medical Therapy of Prostatic Symptoms (MTOPS) study was the first
long-term, large-scale investigation of combination therapy and showed that at 4
years, the combination of doxazosin and finasteride resulted in significantly better
outcomes in terms of overall risk of clinical progression compared with either
5a-reductase inhibitors in prostate disease 395
doxazosin or finasteride alone.
42
Following completion of this study, the Combination
of Avodart
â
and Tamsulosin in Combination (CombAT) study was initiated to inves-
tigate combination therapy using the dual 5ARI dutasteride. CombATwas specifically
designed to enrol men at increased risk of BPH progression by virtue of having a pros-
tate volume 30 cc and a total serum prostate-specific antigen (PSA) level 1.5 ng/
mL.
43
Two-year symptom data from the study have recently been published – these
demonstrate that combination therapy resulted in a significantly greater improvement
in symptoms versus dutasteride from month 3 and tamsulosin from month 9. A signif-
icantly greater improvement from baseline in Qmax was also observed for combina-
tion therapy versus either monotherapy from month 6.
44
Also of note, dutasteride
monotherapy was found to result in a greater improvement in Qmax from month
12 and International Prostate Symptom Score (IPSS) from month 18 than tamsulosin
monotherapy.
45
Four-year data will report on the progression outcomes of AUR and
BPH-related surgery, as well as providing further information on the pattern of
symptoms.
5ARIS IN PROSTATE CANCER RISK REDUCTION
Preliminary but inconclusive evidence for the use of 5ARIs to reduce the risk of pros-
tate cancer came from studies of BPH treatment in which prostate cancer detection
was part of the safety evaluations. No difference in prostate cancer detection was
observed in the finasteride and placebo arms in the PLESS study.
46
However, in the
MTOPS study there was a lower incidence of prostate-cancer-positive biopsies in
the finasteride group (but not the combination therapy group) compared with the pla-
cebo or doxazosin groups.
47
The Prostate Cancer Prevention Trial (PCPT) was the first large-scale study to ad-
dress the influence of finasteride on the development of prostate cancer.
48
It demon-
strated that finasteride significantly reduced the risk of developing prostate cancer by
24.8% versus placebo over a 7-year period. As such, it was the first study to provide
level-1 evidence for the benefit of a 5ARI in prostate cancer risk reduction. Although
an increased incidence of Gleason grade-7–10 cancers was observed in the finasteride
group, the proportions of high-grade tumours in the two treatment arms did not
diverge with time, suggesting an artefactual cause for this observation. In addition,
pathological prognostic factors associated with tumour volume and extent were found
to be lower in the finasteride arm compared with placebo.
49
Given that a >25% re-
duction in prostate volume occurred with finasteride in this study, the most likely ex-
planation for the higher incidence of high-grade tumours in the finasteride arm is that
finasteride improved cancer sampling on biopsy. This hypothesis is supported by pre-
dictions using mathematical modelling
50,51
and by data from a retrospective biopsy re-
view.
52
However, prostate volume changes alone cannot explain the difference
between high- and low-grade tumour detection in the PCPT, since if this were the
case the effect of volume on cancer detection would be expected to be the same
across tumour grades.
Further, a statistically significantly greater sensitivity and area under the receiver
operating characteristic curve for PSA in the detection of prostate cancer has been
observed in the finasteride arm of the PCPT than in the placebo arm, providing evi-
dence of a PSA-driven ascertainment bias.
53
The likely cause of this detection bias is
that finasteride reduced PSA to a lesser extent in men with high-grade cancer than
in men with benign epithelium or low-grade cancer. Because the actual PSA value
was multiplied by a factor of 2.0–2.3 in the finasteride arm to preserve the study blind,
396 R. S. Rittmaster
and adjusted PSA values >4.0 ng/mL resulted in a recommendation of a for-cause bi-
opsy, the differential reduction in PSA would result in more for-cause biopsies in men
with high-grade cancer in the finasteride arm.
Following the initiation of the PCPT, it was argued that the association of the de-
velopment and progression of prostate cancer with increased expression of type-1
5a-reductase provided a strong scientific rationale to investigate a dual 5ARI, such
as dutasteride, in a risk-reduction setting. Retrospective analyses of the incidence of
prostate cancer recorded as adverse events in the three phase-III BPH trials of dutas-
teride revealed that the cumulative incidence of prostate cancer was 50% lower in the
dutasteride group compared with placebo at 27 months (1.2% versus 2.5%,
P ¼0.002).
54
These results prompted the initiation of the Reduction by Dutasteride
of Prostate Cancer Events (REDUCE) study, a 4-year, randomized, placebo-controlled
trial to evaluate the efficacy and safety of daily dutasteride in approximately 8000 men
at increased risk of developing prostate cancer.
55
The design of the REDUCE study
differs from that of the PCPT in several key areas, as shown in Table 2. The REDUCE
entrance criteria were designed to select a population likely to be viewed as optimum
candidates for any future prostate cancer risk reduction strategy. Data from REDUCE
are expected to be available in 2009.
A recent finding of considerable interest from the PCPT was that finasteride sig-
nificantly decreased the overall risk of high-grade PIN by 21% compared with pla-
cebo.
56
Given current thinking that HG-PIN is a pre-invasive intermediate step in
prostate cancer development, this finding supports the hypothesis that 5ARI therapy
may also have benefit in delaying cancer development. Further studies have been ini-
tiated to examine whether 5ARIs could limit progression in men with diagnosed
prostate cancer. The Reduction by Dutasteride of Clinical Progression Events in Ex-
pectant Management (REDEEM) trial is an ongoing 3-year study designed to evaluate
whether dutasteride decreases time to prostate cancer progression in men with
low-risk, localized prostate cancer.
57
This is an important area of research, as ag-
gressive therapy in men with localized prostate cancer can lead to significant treat-
ment complications, such as impotence and incontinence, and may ultimately be
unnecessary in a given patient as the majority are likely to die with the disease
rather than because of it.
58
Given our current inability to accurately define which
men with localized disease are likely to have an adverse outcome from it, use of
dutasteride in men undergoing expectant management for low-risk, localized pros-
tate cancer has the potential to delay disease progression and eliminate the need
Table 2. Key differences in the design of the PCPT and REDUCE prostate-cancer risk-reduction
trials.
48,55
PCPT REDUCE
Study drug Finasteride Dutasteride
Study duration 7 years 4 years
Number of subjects 18,882 8,200
Age 55 years 50 years
Baseline biopsies No Yes (one negative biopsy)
Follow-up biopsies After 7 years At 2 and 4 years
PSA entry criteria <3.0 ng/mL 2.5e10.0 ng/mL
Location US only International
5a-reductase inhibitors in prostate disease 397
for, or extend the time period to, implementation of more aggressive therapy. Over
the next few years, both the REDUCE and REDEEM studies will add much to our
understanding of the role of dual 5a-reductase inhibition in the prostate cancer
setting.
SAFETY AND TOLERABILITY OF 5ARIS
To date, the large-scale clinical studies conducted with finasteride and dutasteride have
demonstrated that both 5ARIs are generally well tolerated during long-term treat-
ment.
36,48,59,60
Sexual adverse events were the most commonly reported class of
drug-related adverse event; these were no more likely to lead to discontinuation of
therapy in the treated groups than the placebo groups. Both 5 mg finasteride and
0.5 mg dutasteride daily cause modest, and comparable, reductions in spermatogene-
sis. These are unlikely to be clinically significant for most patients. However, occasional
patients have marked reductions in spermatogenesis, which are likely to be reversible
once the drug is discontinued.
61
It has been suggested that decreases in androgen
levels may decrease bone mineral density and impact lipid levels.
62
However, no clin-
ically significant changes in bone mineral density, bone metabolism markers or lipid
levels were observed with dutasteride or finasteride during a 1-year placebo-
controlled study.
59
Both finasteride and dutasteride decrease PSA by a mean of approximately 50% af-
ter 1 year, although the variability is large. After 4 years, in men not having a diagnosis
of prostate cancer on study, finasteride decreased PSA by a median of 57%, whereas
dutasteride decreased PSA by a median of 66%.
46,63
In men initiating 5ARI therapy,
a new PSA baseline after 6 months of treatment should be established for assessing
future changes in PSA. In general, PSA should stabilize around a new nadir or decrease
gradually over time in men without prostate cancer who are receiving 5ARIs. It has
been hypothesized that 5ARIs increase the sensitivity of serial PSA measurements
for detection of prostate cancer by suppressing the benign component of PSA secre-
tion. In determining whether or not isolated PSA values fall within normal ranges, it
has been recommended that PSA values should be doubled in patients who have re-
ceived 5ARI therapy for at least 6 months. Although this adjustment does not cause
the serum PSA levels to equal that of a placebo population (whose PSA levels continue
to rise over time), it does preserve the utility of PSA for the diagnosis of prostate
cancer.
63
Practice points
5ARIs have been demonstrated to be effective in reducing LUTS and improving
quality of life and long-term BPH outcomes in men with prostate enlargement.
Level-1 evidence exists for finasteride in reducing the risk of prostate cancer,
and recent studies have indicated that the increase in detection of high-grade
tumours with finasteride in the PCPT probably resulted from ascertainment
biases.
When monitoring PSA in men taking 5ARIs, a new baseline should be obtained
after at least 6 months, and persistent increases in PSA thereafter suggest the
need for further evaluation.
398 R. S. Rittmaster
SUMMARY
Androgens play a key role in the development and maintenance of normal and aber-
rant prostatic growth. It is now understood that DHT is the primary androgen in
the prostate; DHT is synthesized from testosterone under the catalysis of the 5a-re-
ductase isoenzymes. Inhibition of these isoenzymes therefore represents a rational ap-
proach for the development of pharmacological therapy for BPH and prostate cancer.
This led to the discovery and clinical development of first finasteride, a type-2 5ARI,
and subsequently dutasteride, a dual 5ARI. Both compounds have demonstrated ben-
efits in the treatment of symptomatic BPH and in the prevention of long-term disease
progression. Both agents are safe and well tolerated, and are therefore suitable for
long-term clinical use. Finasteride has also demonstrated efficacy in the primary risk
reduction of prostate cancer, while the ongoing REDUCE study is evaluating the
effects of dutasteride in a similar setting, but with a different risk profile. The effect
of dutasteride in reducing progression in low-risk, localized prostate cancer is also be-
ing investigated in the ongoing REDEEM study. Given that type-1 5a-reductase appears
to play a role in the development and progression of prostate cancer, these ongoing
studies will add much to our understanding of dual 5a-reductase inhibition in the pros-
tate cancer setting.
CONFLICT OF INTEREST
Dr Rittmaster is an employee of GlaxoSmithKline.
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