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-Reductase1
Departments of Physiology and Biophysics (A.S.W., R.C.D., L.N.T., R.S.R.), Biochemistry (C.B.L.) and Medicine (R.S.R.), Dalhousie University, Halifax, Nova Scotia, Canada, B3H 4H7
Address all correspondence and requests for reprints to: A. Stuart Wright, Department Physiology and Biophysics, Tupper Building, Dalhousie University, Halifax, Nova Scotia, Canada, B3H 4H7. E-mail: aswright{at}is2.dal.ca
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-reductase (5-R) to be
maximally active in the prostate. The present study was designed to
determine the relative potency of T and DHT on regrowth of the
involuted prostate and to elucidate the role of 5-R in the growing
prostate. To create dose-response curves for intraprostatic T or DHT,
rats were castrated for 2 weeks to allow their prostates to fully
regress and then given T implants of various sizes in the presence or
absence of the 5-R inhibitor, finasteride. Markers for
androgen effects on regrowth of the prostate were prostate weight, duct
mass (a measure of secretory activity) and DNA content (a measure of
cell number). To assess the relative uptake of T and DHT by the
prostate, a comparison was made of intraprostatic DHT levels resulting
from T and DHT implants. In the prostate, 1.6–1.9 times more T than DHT was required to achieve a half-maximal response for each of the three markers of prostate regrowth. The dose-response curves revealed that thresholds for intraprostatic T and DHT had to be attained before significant growth was observed. The threshold for T was 2- to 3-fold greater than that for DHT. However, at high intraprostatic concentrations, the effects of T mimicked those of DHT. When the relationship between serum T levels and prostate regrowth was considered, 13 times more serum T was required for half-maximal prostate regrowth when its conversion to DHT was blocked by finasteride. This is partly due to decreased androgen accumulation in the prostate when T was the major intraprostatic androgen. Finally, T or DHT implants in the absence of finasteride resulted in similar intraprostatic DHT levels, indicating that uptake of each serum androgen into the prostate was similar. However, to achieve similar levels of DHT or T in serum, much larger DHT pellets were needed, suggesting more rapid metabolism of DHT in tissues other than the prostate.
We conclude that the role of 5-R is 2-fold: it converts testosterone
into a modestly more potent androgen and enhances prostatic
accumulation of androgen. DHT, in principle, could serve equally well
as T as the circulating androgen, although the rate of DHT production
would have to be considerably higher to counter the apparent rapid
clearance from serum. In addition, we hypothesize that T has arisen as
the major circulating androgen instead of DHT because it can be
aromatized to estradiol, which itself has important roles in male
reproductive function and bone physiology.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-reductase (5-R) for
maximal androgenic activity in the prostate (1, 2). Inhibition of
5-R using pharmacological agents such as finasteride
reduces the intraprostatic DHT concentration to that seen in castrated
animals. Initial studies using a single dose of T replacement in an
androgen-depleted environment have shown that inhibition of 5-R
inhibits cell proliferation in the rat prostate (3, 4, 5, 6, 7, 8), tumor explants
(9, 10) and prostate cancer cell lines (11, 12). However, inhibition of
5-R in rats also results in a 20-fold increase in the intraprostatic
concentration of T (13). The high level of intraprostatic T is the
reason 5-R inhibitors do not cause the same degree of prostate
regression as does castration. In a previous study, we examined the
relative potency of intraprostatic T and DHT in preventing regression
of the prostate (14). T and DHT were equipotent in their ability to
suppress apoptosis, but DHT was 2–3 times more potent than T in
preventing epithelial cell atrophy after castration. However, it was
difficult to explain the profound effects of 5-reductase deficiency
by the small difference in potency between the two androgens. The
present study examines the relative potency of T and DHT on prostate
regrowth after castration, in order to elucidate the role of 5-R in
stimulation of prostate regrowth. Rats were first castrated and their
prostates allowed to regress for 2 weeks. The animals were then
implanted with varying sizes of T pellets, in the presence or absence
of finasteride. In the absence of finasteride
a dose-response for the potency of DHT on prostate regrowth was
generated, while in the presence of finasteride, DHT is
suppressed to near castrate levels at all concentrations of T used and
a dose-response for T resulted. Of particular importance was the
ability of T or DHT in the prostate to stimulate proliferation of that
organ. In the assessment of the relative potency of these two
intraprostatic androgens, we compared not only the levels of T and DHT,
but also the relationship between serum and prostatic androgen
levels. The other issue examined in our study is the question of why T, and not DHT, is the major circulating androgen. It has been speculated that uptake of DHT by the prostate may not be as efficient as uptake of T (15). Indeed, Pollard et al. demonstrated antiandrogenic effects in rats supplemented with DHT (16, 17). Intact L-W rats predisposed to developing prostate cancer were supplemented with equal concentrations of either T or DHT for 14 months (16). Prostate adenocarcinomas developed in 24% of the T-supplemented rats but not in the DHT-supplemented rats. In a clinical study of hypogonadal men supplemented with DHT, prostate size was observed to decrease after a mean time of 1.8 yr of treatment (18). Are these observations the result of an impaired capacity of exogenous DHT to accumulate in the prostate—or do they reflect the overall lower levels of circulating androgen because tissues such as muscle metabolize DHT more rapidly than T ? To answer these questions, we compared the ability of DHT and T pellets to serve as precursors for intraprostatic DHT accumulation in the prostates of castrated rats.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-R inhibitor finasteride (Proscar,
Merck Sharp & Dohme Research Laboratories, Rahway, NJ) to
inhibit intraprostatic conversion of T to DHT. Two-week castrated rats
were implanted with T pellets of the following doses: 0.1, 0.3, 0.5,
1.0, 2.5, 5.0, and 15.0 mg. The numbers of rats per group for the
intraprostatic T dose-response were 11, 11, 11, 11, 9, 8, and 6,
respectively. For the intraprostatic DHT dose-response experiment, 0.1,
0.3, 0.5, 1.0, 5.0, and 15.0 mg T pellets were used and the numbers of
rats per group were 11, 11, 19, 7, 6, and 6, respectively. Rats were
killed 7 days after implantation while the prostates were actively
growing. In a separate experiment, DHT pellets were implanted in 2-week
castrated rats. There were five rats per group, and the doses used were
0.1, 0.3, 0.5, 1.0, 5.0, 15, 30, and 60 mg. All pellets were implanted
sc. into the subscapular region under anesthesia.
Finasteride-treated rats were given 40 mg/kg/day sc.
injections in 1 ml sesame oil with 10% ethanol vehicle. Rats were
killed via CO2 asphyxiation, exsanguinated, and the
prostates were removed, weighed, and prepared for histological
examination or immediately frozen in liquid nitrogen for measurement of
T and DHT concentrations.
Androgen concentration measurements
Intraprostatic T and DHT levels were measured in 100–200 mg
samples of homogenized prostate tissue by RIA after extraction in
Delsal’s solution (4:1 methylal: methanol). The androgens were
purified over silica columns and separated by celite chromatography as
previously published (19). Procedural recoveries (mean ±
SD) were 70 ± 7% for T and 65 ± 11% for DHT.
Mean assay sensitivities (assuming a mean recovery) were 0.62 nmol/kg
tissue (0.18 ng/g) for T and 0.72 nmol/kg tissue (0.21 ng/g) for DHT.
All reported T and DHT measurements were within the working range of
the assay. Interassay coefficients of variation were 11.1% for T and
9.9% for DHT.
Morphometrics
Ventral prostates were fixed by immersion in buffered 10%
formalin, embedded in paraffin, and sectioned at 5 µm for
histological analysis. Tissues were stained with hemotoxylin and eosin
to visualize prostate architecture. Duct area was determined using
image analysis equipment. A JVC RGB video camera (model no. TK-1070U,
Elmwood Park, NJ) and Truevision NuVista+ frame grabber card
(Indianapolis, IN) were used to capture microscopic images (100x
magnification) to a Macintosh computer. The ducts were isolated using
Adobe Photoshop (Adobe Systems, Inc., Mountain View, CA)
and the area determined on a Macintosh computer using the public domain
NIH Image 1.61 program (developed at the U.S. National Institutes of
Health and available on the Internet at
http://rsb.info.nih.gov/nih-image/). Duct mass, a measure of secretory
activity, was determined by multiplying the duct area from the captures
by the prostate weight. Analysis was accomplished sampling five random
sections per slide from different regions of the prostate and three
prostates per group.
DNA/prostate measurements
Total tissue DNA mass was measured using a modified method of
Burton et al. (20) as previously described (13).
Statistics
Values are expressed as the mean ± SEM.
Statistical analyses of significance were performed by ANOVA using
StatView (Abacus Concepts, Berkeley, CA) on a Macintosh
computer (P < 0.05 was considered to be statistically
significant). Fisher’s protected least significant difference (PLSD)
test was used for posthoc pairwise comparisons.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-R in androgen-dependent growth of the
involuted rat prostate, intraprostatic dose-responses for T and DHT
were created. To accomplish this, T pellets were implanted into two
groups of rats that were castrated 2 weeks previously. One of the
groups was also treated with finasteride using a dose
previously shown to inhibit prostatic 5-R activity (21). The levels
of intraprostatic T and DHT are reported in Table 1
. Normal rat prostate DHT levels were
19.2 ± 1.2 ng/g and T levels were 0.9 ± 0.1 ng/g. For
normal rats treated with finasteride, intraprostatic T
levels were increased to 16 ± 2 ng/g while DHT was suppressed at
0.5 ± 0.3 ng/g. In the intraprostatic DHT dose-response
experiment, DHT levels ranged from 0.5–25.8 ng/g, whereas T levels
remained at 0.4–0.8 ng/g. In the intraprostatic T dose-response
experiment, finasteride blocked the formation of DHT
resulting in an intraprostatic T range from 0.5–24.6 ng/g, while DHT
remained low at 0.4–1.1 ng/g. In the DHT and T dose-response groups,
the respective corresponding T and DHT levels were suppressed below the
thresholds for prostate growth (Table 1, Fig. 1). Consequently, only the major
intraprostatic androgen is recorded in each dose-response curve (Fig. 1). It is worth noting that in the face of increasing T,
finasteride was able to maintain suppression of
intraprostatic DHT levels.
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Figure 1
illustrates the relationship between the intraprostatic T or
DHT concentrations and the markers for growth of the involuted
prostate. For duct mass, DNA content per prostate, and prostate weight,
a threshold or minimum concentration of T and DHT was needed before
significant responses were observed. The threshold for each of the DHT
dose-response curves was approximately 3 ng/g, whereas for the
intraprostatic T dose-responses, the threshold was between 5 and 10
ng/g. Despite this difference, once this threshold was reached, the
slopes of the response vs. the androgen concentration curves
were similar for intraprostatic T and DHT. It should also be noted that
at high concentrations the ability of T to support prostate hypertrophy
and hyperplasia was similar to DHT.
Comparison of the half-maximal responses of prostate secretory
activity, DNA content per prostate, and prostate weight from the
dose-response curves reveals the potency difference between
intraprostatic T and DHT. Table 2 lists
the concentrations of T and DHT required to achieve a half-maximal
response of the above-mentioned markers of prostate growth. According
to this table, DHT appears to be 1.6–1.9 times more potent than T.
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). In normal intact rats, the serum T level was
286 ± 23 ng/dl, and in the intact rats treated with
finasteride, the serum T level was unchanged at 307
± 72 ng/dl. In the castrated rats, the serum T levels were at the
detection limit of the assay (5 ng/dl). For the dose-response
experiments, in the absence of finasteride, the serum T
range was 5–500 ng/dl, and in the presence of
finasteride, it was 5–516 ng/dl. The data in Fig. 2 show that DHT accumulates
preferentially in the prostate (compared with T) at low serum T
concentrations. However, as serum T levels rise, the advantage of
5-R for accumulation of androgen in the prostate diminishes.
Half-maximal prostatic accumulation of DHT occurs at a serum T
concentration of approximately 49 ng/dl, whereas half-maximal
intraprostatic accumulation of T in the presence of
finasteride requires 4.6 times more serum T (227 ng/dl),
(Table 2).
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illustrates the results when
prostate growth markers are expressed in terms of serum T levels. In
the absence of 5-R inhibition, the dose-response curves show a
dramatic increase in prostate secretory activity, DNA content, and
weight at low serum T levels. After the initial rise, the effect
reaches a plateau where increasing serum T concentration only results
in modestly increased levels of hypertrophy and hyperplasia. In the
presence of 5-R inhibition, significantly higher T levels in serum
were needed before growth was observed.
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presents the half-maximal
responses in the markers of prostate growth as a function of serum T.
Considerably higher T levels are needed in the presence of the 5-R
inhibitor. Thus, expressing the results in terms of circulating hormone
levels reveals that inhibiting 5-R hinders prostate growth up to
16-fold except at high levels of serum T. Expressing the half-maximal
responses as a function of serum T takes into account the potency
difference between T and DHT in the prostate (1.6- to 1.9-fold) as well
as the concentration difference in serum T needed to accumulate
androgens in the prostate (up to 4.6-fold).
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, the intraprostatic DHT
concentration is plotted as a function of serum DHT, from DHT
pellet implants, and serum T, from T pellet implants. The dose-response
curves for serum T and serum DHT are virtually indistinguishable. This
demonstrates that DHT can accumulate in the ventral prostate directly.
However, to achieve similar prostate and serum androgen concentrations,
larger DHT pellets were required (compared with T pellets). This likely
reflects a more rapid metabolic clearance rate for DHT in serum by
tissues other than the prostate (24, 25). The results are
presented in Table 4.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-R inhibition at all levels of serum
T. This implies that the effects associated with
finasteride treatment are mediated by the high
concentration of T and not by the low concentration of DHT observed
under such conditions. The concept of a critical threshold for DHT was
first established by Kyprianou et al. (26), in experiments
in which 2-week castrated rats were supplemented with T-filled SILASTIC
brand silicon implants (Dow Corning, Midland, MI) of
varying lengths. It was observed that increases in prostate cell number
occur only after a concentration of DHT that was 12% of normal. In our
study, the threshold for DHT in the prostate was approximately 17% of
normal DHT concentration.
It is evident that 5-R amplifies the androgenic signals in the
prostate. However, the potency difference between intraprostatic T and
DHT does not adequately explain the role of 5-R in the prostate. The
ability of each androgen to accumulate in the prostate from serum T
illustrates another aspect of the function of 5-R. This becomes
clearer when we express the markers of prostate regrowth in terms of
serum T levels. The serum T concentration required for the half-maximal
responses of prostate regrowth is 10.9–15.8 times higher in the
presence of finasteride than in its absence. In contrast,
the potency difference based on the intraprostatic levels of the two
androgens is only 1.6- to 1.9-fold. Expressing the results in terms of
the serum T levels, however, encompasses both the intraprostatic
potency and the enhanced ability of the prostate to accumulate and
retain DHT. The most likely explanation for this observation is that
DHT has a higher affinity for the androgen receptor (AR) and is more
capable of stabilizing the AR complex (23, 27). Stabilizing the
receptor complex against degradation means that DHT is able to increase
the time it is bound within the nucleus, and with a lower turnover
rate, less serum T is needed to maintain the supply of androgen within
the prostate.
The influence of the ligand on nuclear receptor structure and action is beginning to be understood (28). An early study suggested that T bound to the AR was 10- fold less potent than the DHT-AR complex in activating expression of an androgen-responsive MMTV-promoter-reporter gene construct (22). However, the specific effects of particular ligand-AR complexes are likely to vary depending on the promoter context and cell type specificity of sensitive genes. In a recent example, T appears to be more effective than DHT in repression of a particular androgen target gene, TDD5 (29). Also, Avila et al. (30) have identified genes in the prostate that are in fact modulated differently by finasteride treatment. Using differential display PCR, they have classified genes that are up-regulated only in intact rats and genes that are upregulated only with finasteride treatment. Differential effects of T and DHT on the expression of various genes are most likely due to different conformations of the liganded AR with resulting differences in AR-DNA and AR-protein interactions at androgen response elements associated with specific genes. In complex responses such as promotion of growth, or inhibition of apoptosis, many different androgen-responsive genes are probably involved.
Because DHT is more potent than T for most endpoints, the question
arises as to why DHT is not the major circulating androgen in males.
The present study shows that serum T and DHT can serve equally well as
precursors for intraprostatic DHT in castrated rats. However, an
important disadvantage for the role of DHT as the major peripheral
androgen is that it is not aromatizable to estrogen. Estrogen has been
demonstrated to be essential for normal bone maturation in male rodents
and men and for normal fertility in male rodents (31, 32, 33, 34). Another
disadvantage to having DHT as the major circulating androgen is its
rapid metabolism in tissues other than the prostate. For example, in
muscle, T has been considered to be the active androgen because of the
low 5-R activity and low DHT levels in this tissue (35, 36).
Conversion of DHT to androstanediol, catalyzed by 3-hydroxysteroid
oxidoreductase, predominates in muscle, whereas the reverse reaction
predominates in prostate (24). Therefore, given the large mass of
muscle tissue in relationship to prostate tissue, it is not surprising
that the resulting serum DHT concentrations are much lower than the
those of T.
In conclusion, our data suggest that the major roles for prostatic
5-R are not only to convert T to a more potent hormone but also to
promote androgen accumulation at low serum T levels. The difference in
potency of T and DHT with regard to prostate regrowth is not very large
with respect to intraprostatic androgen concentrations but is much
greater if serum T levels are considered.
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Footnotes |
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Received February 16, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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) was achieved, while in the absence of
finasteride treatment, a dose-response for intraprostatic
DHT resulted (closed triangles, 
). The animals were
killed 7 days postimplantation. The horizontal line indicates the
half-maximal effect on each parameter of prostate growth. The number of
animals each point represents: 3–4 (A), 2–3 (B), and 6–11 (C). The
r-values for the linear curves were: (A) 0.95 DHT dose-response and
0.97 T dose-response; (B) 0.90 DHT dose-response and 0.92 T
dose-response; (C) 0.96 DHT dose-response and 0.95 T dose-response.
).
Measurements represent three animals per dose group.