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Medical Research Council Group in Molecular Endocrinology, CHUL Research Center and Laval University, Québec G1V 4G2, Canada
Address all correspondence and requests for reprints to: Dr. Mohamed El-Alfy, Medical Research Council Group in Molecular Endocrinology, CHUL Research Center, 2705 Laurier Boulevard, Québec G1V 4G2, Canada. E-mail address: mohamed.el-alfy{at}crchul.ulaval.ca
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Introduction |
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-reductase type 1 (17, 18) and type 2 (19, 20).
The enzyme 3ß-HSD is essential for the biosynthesis of all classes of
hormonal steroids, namely progesterone, glucocorticoids,
mineralocorticoids, androgens, and estrogens. The 3ß-HSD enzyme is
present in the adrenal, testis, ovary, and placenta, as well as in a
long series of peripheral intracrine tissues, including the prostate,
breast, liver, and skin (21, 22). The 3ß-HSD converts
DHEA into androstenedione (4-dione), whereas the formation
of testosterone from 4-dione and DHT from 5-androstane-3, 17-dione
(A-dione) and their respective backward reactions are catalyzed by
17ß-HSDs. The five human 17ß-HSDs characterized so far show only
approximately 20% homology in their amino acid sequences. Moreover,
the various 17ß-HSDs differ markedly in their tissue distribution and
substrate specificity (23, 24, 25). In fact, we have recently shown, using
intact transfected cells in culture, that the activity catalyzed by
each type of 17ß-HSD is unidirectional. The recently cloned 17ß-HSD
type 5 (16) selectively catalyzes the reduction of 4-dione into
testosterone and 4-dione into DHT. In peripheral intracrine tissues,
the various levels of expression of types 1, 2, 4, and 5 17ß-HSD
activities play a critical role in regulating the formation (types 1
and 5) or inactivation (types 2 and 4) of active estrogens and
androgens.
To obtain precise information on the cellular distribution of type 5 17ß-HSD and gain a better knowledge of the role of this enzyme in the human prostate, we performed in situ hybridization and immunocytochemical localization studies in human hyperplastic prostatic tissue [benign prostatic hyperplasia (BPH)]. Normal human prostate tissue and the epithelial prostate cell line (PrEC) were also investigated by immunostaining. In the same series of experiments, the immunocytochemical localization of 3ß-HSD was examined to compare the distribution of the two enzymes that are both involved in the biosynthesis of androgens from DHEA. To determine the site(s) of action of the locally produced androgens, we have also identified the immunocytochemical localization of the androgen receptor (AR).
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Materials and Methods |
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Cultured cells
Normal prostate epithelial cells PrEC 5500–1 were cultured in
PrEGM medium (Clonetics, Walkersville, MD) and harvested, after
the third passage, using a rubber policeman. The cells were then fixed
in 2% glutaraldehyde, 4% formaldehyde, and 3% dextran in 0.05
M phosphate buffer for 20 min and centrifuged at 700 rpm
for 5 min. After removing the supernatant, 2% agarose in 0.05
M phosphate buffer was added to the pellet at 55 C (the
volume of agarose was twice the volume of the pellet). After mixing the
cells with agarose, the pellet was solidified at 4 C and immersed in
the same fixative for 2 h, then washed, processed, and paraffin
embedded.
In situ hybridization
Two different procedures were used for in situ
hybridization of BPH tissue. In the first one, 10-µm sections were
cut from frozen tissue with a cryostat and processed as previously
described (26). The second procedure will be described in detail
elsewhere (El-Alfy et al., unpublished data). In brief,
thick paraffin sections (20-µm) were cut, and the unmounted sections
were deparaffinized in toluene. The sections were subsequently
rehydrated; postfixed in 2% glutaraldehyde, 4% formaldehyde, and 3%
dextran in 0.05 M phosphate buffer; and washed in the same
buffer containing 7.5% glycine. Hybridization of the floating sections
was performed overnight at 40 C with a 3H-UTP
riboprobe, as previously described (27). After hybridization, they were
postfixed in osmium tetroxide, flat-embedded in Epon, and cut at 0.7
µm with an ultramicrotome. Both frozen (10-µm) and semithin
(0.7-µm) sections were coated with liquid photographic emulsion
(Kodak NTB-2, Eastman Kodak Co., Rochester, NY) and
processed after 14 days (semithin sections) or 28 days (frozen
sections) of exposure.
Sense and antisense riboprobes were generated by in vitro transcription from the p-Bluescript phagemid containing a cDNA insert of 35 nucleotides of the human type 5 17ß-HSD. [35S]- and [3H]-UTP riboprobes were used for hybridization with the frozen and floating deparaffinized sections, respectively.
Immunocytochemistry
Twelve paraffin-embedded BPH samples, four normal prostate
specimens, and PrEC cells in paraffin blocks were serially cut at 4
µm. Sections were incubated overnight at 4 C, with the human type 5
17ß-HSD antiserum diluted at 1:1000 in Tris-saline, pH 7.6. The
sections were then washed and incubated at room temperature for 4
h with peroxidase-labeled goat antirabbit 
-globulin (Hyclone Laboratories, Inc., Logon, UT), diluted 1:500, as previously
described (28). Endogenous peroxidase activity was eliminated by
preincubation with 3% H2O2 for 30 min, and
peroxidase was then revealed during incubation with 10 mg
3,3-diaminobenzidine in 100 ml Tris-saline buffer containing 0.03%
H2O2. The intensity of staining was controlled
under the microscope. The sections were then counterstained with
hematoxylin. On other sections, immunostaining was performed using a
commercial kit (Vectastain ABC Kit; Vector Laboratories, Inc., Burlingame, CA), and diaminobenzidine was
used as the chromogen to visualize the biotin streptavidin-peroxidase
complex. A microwave retrieval technique was applied for the AR
staining (29). Control experiments were performed on adjacent sections
by substituting nonimmunized rabbit serum (1:1000). In the case of type
5 17ß-HSD antiserum (diluted 1:1000), immunoabsorption with an excess
(10-6 M) of the synthetic peptide used to
raise the antibodies was also performed. The number of stained cells
(type 5 17ß-HSD) and nuclei (ARs) were counted from colored
photographs and their number presented in Table 1
. The intensity of staining was compared
and evaluated between the different stained cell types of the prostate
on the same section. Similarly, the density of silver grains was
compared between the labeled cells on the same section. The intensity
of immunostaining and in situ hybridization reaction was
presented in Table 2. Paraffin sections
of cultured cells were immunostained, using type 5 17ß-HSD antiserum
as mentioned above, and the number of immunostained cells presented as
a percentage of stained cells.
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Specificity of the antiserum was examined by immunoblot analysis. In
brief, human embryonal kidney cells (293) were transfected with CMV-neo
vectors expressing human type 5 17ß-HSD, types 1 and 3 3-HSD and
types 1 and 2 5-reductase, respectively. Stable transfectants were
selected by their resistance to 107 M G-418.
Positive clones were confirmed by their ability to efficiently
transform the appropriate substrate (16). Forty micrograms of protein
of the homogenate of each cell line were electrophoresed on a 5–15%
SDS-polyacrylamide gel, as described (30), before being transferred to
the nitrocellulose filter using a Bio-Rad apparatus for 4 h at 60
V. The blot was treated 3 times with 5% fat-free milk in PBS
containing 0.1% Nonidet P-40 for 30 min. The antiserum developed
against the type 5 17ß-HSD peptide was diluted to 1:1000, and the
blot was then incubated at 4 C for 18 h in the diluted antiserum.
The blot was then washed three times with PBS containing 5% fat-free
milk and 0.1% Nonidet P-40. After incubation with horseradish
peroxidase-conjugated antirabbit IgG in solution for 2 h, the
membrane was washed, and bound antibodies were detected with ECL
detection reagents (Amersham, Oakville, Ontario,
Canada), and finally, the membrane was exposed to Hyperfilm.
3ß-HSD. The antiserum used for immunocytochemical studies was raised by immunizing rabbits with purified human placental 3ß-HSD (4). This antiserum has been widely used to localize the enzyme in tissues of several species, including the human (31).
AR. AR rabbit antiserum was generated against a synthetic peptide corresponding to the first 20 amino acid residues of the N-terminal domain of the human and rat AR. The antiserum was purified by immunoprecipitation and did not show any cross-reactivity with estrogen or progesterone receptors (32). This antiserum was kindly provided by Dr. Théo H. van der Kwast, Department of Pathology, Erasmus University Rotterdam, The Netherlands.
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Results |
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). In the
fibromuscular stroma, none (or only few) silver grains are located over
smooth muscle cells, whereas the fibroblasts dispersed throughout the
stroma or in association with the wall of blood vessels are well
labeled (Fig. 1c). Interestingly, the endothelial cells lining blood
vessels are strongly labeled. The smooth muscle cells and fibroblasts
of the tunica media and adventitia show variable labeling intensity.
When the hybridization was performed using 3H-labeled sense
riboprobe as control, only a few scattered silver grains were detected
over the epithelium (Fig. 1b) and blood vessels (Fig. 1d). The results
obtained using [35S]-UTP riboprobes (not shown) were
found to be similar to the above mentioned results.
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, immunoblot analysis indicates that the
antiserum specifically reacts with type 5 17ß-HSD. In fact, no
cross-reactivity was detected, either with types 1 or 3 3-HSD (which
share 84% and 86% identity with type 5 17ß-HSD, respectively) or
with types 1 and 2 5-reductase, two enzymes which are abundant in
prostatic tissue (17, 33).
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, a–c; and 4, a and b). Some variation
in the distribution and intensity of immunostaining was observed
between the twelve BPH specimens examined. A similar degree of
variation was found between the normal prostate specimens, and the
overall pattern was similar between normal and BPH prostatic tissues.
The variation in staining of the epithelium lining the tube-alveoli was
observed, not only between the different specimens but also between the
tube-alveoli of the same specimens. A constant finding was the positive
reaction detected in the stromal fibroblasts, whereas the smooth muscle
cells were not stained (Figs. 3, a–c; and
4, a, b, and d). Strong staining was
consistently found in the basal cells of the epithelium (Figs. 3a, 4a, and 5a). In contrast, the luminal secretory cells exhibited highly
variable and usually low immunoreactivity. In fact, in most alveoli
(about 85%), no luminal cells were labeled (Figs. 3a and 4a), whereas
about 10% of alveoli contained a low detectable (but positive)
reaction of all luminal cells (Fig. 3b), the basal cells being always
strongly labeled. In some alveoli (about 5%), labeling of few luminal
cells and all basal cells (Table 1
) was found (Figs. 3c and 4b).
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). The endothelial cells of small (Fig. 4e) and large (Fig. 4, e–g)
blood vessels were strongly immunoreactive. The staining reaction was
variable in the smooth muscle cells of the tunica media, whereas
fibroblasts of the tunica adventitia were intensively stained. Veins
appeared strongly labeled because of the large number of fibroblasts in
their walls (Fig. 4e). In arteries, the tunica media was lightly
stained (Fig. 4, f and g), whereas the tunica adventitia was well
stained (Fig. 4f).
When the paraffin sections of cultured epithelial cells were examined
after immunostaining, using type 5 17ß-HSD antibody, 58% of these
cells were found to be positively stained (Fig. 3d).
3ß-HSD Distribution. The results obtained, after
immunostaining with antibody to 3ß-HSD, were found to be very similar
to those generated with the type 5 17ß-HSD antiserum (Fig. 5, a and b). Although the staining
reaction was generally weaker for 3ß-HSD, the cellular distribution
of the enzyme corresponds very well to that described above for type 5
17ß-HSD. In the glandular epithelium of the prostate, all the basal
cells were generally labeled; whereas in the luminal cells, the
staining was variable, being intense in some cells and weak or absent
in most others. In the stroma, the staining was restricted to the
cytoplasm of fibroblasts. As observed for type 5 17ß-HSD, specific
immunolabeling was found in the endothelial cells and fibroblasts of
blood vessel walls, including arteries, veins, and capillaries. In all
the 3ß-HSD-containing cells, the staining was restricted to the
cytoplasm, no significant nuclear staining being detected.
AR distribution. The AR appears exclusively localized in the
nuclei of prostate cells in all the specimens examined. In the
epithelium, immunostaining is detected in almost all the nuclei of the
luminal cells, whereas most of the basal cell nuclei do not exhibit
positive staining (Fig. 5c and Table 1). In the stroma, the majority of
nuclei of the fibromuscular cells are labeled, but unstained nuclei of
smooth muscle cells are also observed (Fig. 5d and Table 1). In the
blood vessels, several nuclei of the endothelial cells lining the lumen
are positive, but some display no reaction (Fig. 5e). In the tunica
media of the arteries, most of the nuclei of the smooth muscle cells
are stained, whereas some remain negative (not shown). Comparable
results were obtained for the nuclei of fibrocytes of the tunica
adventitia.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In the present study, we have used two complementary approaches, namely
in situ hybridization (using BPH specimens) and
immunocytochemistry (using BPH, normal prostate tissues, and cultured
epithelial cells) to identify the cells that express type 5 17ß-HSD
in the human prostate. This enzyme was found mainly in the basal cells
of the tube-alveoli, the fibroblasts of the stroma and blood vessels,
and in the endothelial cells of the blood vessels (Tables 1 and 2).
This double approach permits us to identify not only type 5 17ß-HSD
messenger RNA (mRNA) but also the enzyme itself. The present data are
in agreement with results from this laboratory, which indicated the
presence of androgenic 17ß-HSD activity in human and rhesus monkey
prostates (38).
The stratified epithelium lining the tube-alveoli is divided into two
layers, namely the basal layer made of low cuboidal cells and a layer
of columnar secretory cells (luminal cells). It is generally believed
that prostatic stem cells are located in the basal cell layer (see Ref.
41). As revealed by both in situ hybridization and
immunocytochemistry, the basal cells are expressing type 5 17ß-HSD at
a much higher level than the luminal cells. In fact, whereas many
luminal cells exhibited some detectable hybridization signal, they have
shown a high degree of variation and usually low level of
immunostaining (Figs. 3c and 4b). On the other hand, the majority of
alveoli contained only strongly labeled basal cells (Figs. 3a and 4a).
However, in a few alveoli, staining was detectable either in some
luminal cells (Figs. 3c and 4b) or in all of them (Fig. 3b). This
variable staining in luminal cells might be explained by variations in
the biosynthetic activity among alveoli or among different luminal
cells in the same alveolus. It is quite possible that the low level of
the protein in an unknown proportion of luminal cells cannot be
detected by immunocytochemistry. It is noteworthy to mention that very
similar results were obtained with the antibody against 3ß-HSD.
The cultured epithelial cells PrEC 5500–1 have shown approximately the same pattern of expression of type 5 17ß-HSD as the epithelial cells of BPH and normal prostate tissues. We assumed that the cultured epithelial cells are a mixture of basal and luminal cells. Therefore, it is not surprising to find that only 58% of these cells expressed the enzyme.
It has been reported that types 1 and 2 5-reductases are produced by
both epithelial and stromal cells in the prostate (33, 42, 43, 44). Using
immunocytochemistry, Eicheler et al. (45) have shown that
staining for type 2 5-reductase could be seen in both basal and
luminal epithelial cells. On the basis of studies performed with human
prostatic in vitro models, it has been suggested that the
basal cells exert a stem cell role (46, 47, 48). On the other hand,
in vivo studies performed in the rat prostate during
maturation have established that both basal and secretory luminal cells
are self-replicating cell types (49). The presence of type 5 17ß-HSD,
3ß-HSD, and 5-reductase isoenzymes in the basal cells suggests
that this cell type is actively involved in androgen production and
cannot be considered as being only a precursor of the luminal secretory
cells.
Using cells transfected with the cDNAs of different types of 17ß-HSD,
Luu-The et al. (50) have shown that types 1 and 3 17ß-HSD
catalyze the reduction of E1 to E2 and 4-dione to testosterone,
respectively. They have also shown that these enzymes are substrate-
and orientation selective. In fact, type 3 and 5 17ß-HSDs have the
same selective function, but type 3 was detected only in the testis
(14) and was not found in the human prostate (51). Therefore, in the
prostate, the reduction of 4-dione to testosterone is probably caused
by type 5 17ß-HSD. Beause type 5 17ß-HSD and 3ß-HSD are both
highly expressed in basal cells, whereas the AR is mainly present in
luminal cells (Fig. 5c and Table 1), it is tempting to suggest that
testosterone synthesized in the basal cells reaches the luminal cells
in a paracrine fashion, to be ultimately transformed into DHT in the
luminal cells, where the androgenic action is exerted and AR is highly
expressed. DHT, made in the luminal cells by the action of
5-reductase, would then exert its action in the luminal cells
themselves, thus meeting the definition of intracrine activity (1, 52).
The involvement of two cell types in the biosynthesis of steroids has
already been shown to occur in the ovary. In fact, in the ovary, C19
steroids (4-dione and testosterone), synthesized by theca interna
cells, are transferred to granulosa cells, where they are aromatized
into estrogens (53). The present data suggest the possibility of a
similar two-cell mechanism of androgen formation in the human prostate:
testosterone is first synthesized in the basal cells before diffusing
into the luminal cells, where transformation into DHT occurs.
In the present study, the fibroblasts present in the stroma, as well as
those associated with blood vessels, are shown to contain type 5
17ß-HSD mRNA, as well as the immunoreactive type 5 17ß-HSD and
3ß-HSD enzymes. The two types of 5-reductase have also been
detected in this cell type by various techniques (33, 45, 54, 55). The
role of the steroidogenic enzymes in fibroblasts remains to be
established, but because ARs are present in the nuclei of most stromal
cells (Table 1), it is likely that DHT could act in the fibroblasts
themselves (intracrine action) to modulate the activity of these
cells.
The previous study by Leav et al. (56) has shown that, in
normal prostate, basal cells contained the mRNA for AR but lacked an
immunodetectable receptor, whereas in the luminal cells, both mRNA and
immunodetectable receptor were present. These authors have also stated
that AR localization in BPH was identical to that observed in normal
prostate. Similarly, Loda et al. (57) found that the nuclei
of the luminal and the majority of stromal cells were positive to AR
antibody in hyperplastic, as well as normal prostatic glands. They have
also found that primary (as well as metastatic) prostate carcinomas
show nuclear staining for AR. Ruizeveld De Winter et al.
(58), using AR antibody, found that the proportion and the intensity of
immunostained human prostate tumor cells decreased in the more
aggressive tumors. Bonkhoff and Remberger (59) found that the basal
cells also express nuclear AR in normal and hyperplastic tissue.
However, the receptor was most frequently expressed at lower levels in
the basal cells, compared with the staining intensity detected in
secretory luminal cells. Iwamura et al. (60) found that AR
immunostaining was localized to the nuclei of luminal cells but was
weak or absent in basal cells and of variable intensity in the stromal
cells. In the present study, whereas 94% of luminal cells expressed
nuclear AR, only 37% of basal cells were stained (Table 1), and their
staining intensity was lower than that of luminal cells (Table 2). The
majority (66%) of fibromuscular stromal cells also expressed AR. The
findings of the present study are thus in agreement with previous
studies performed in human, rat, and mouse tissue (61, 62, 63). Because the
stroma/epithelium cell ratio is higher in the hyperplastic prostate
(64), it can be hypothesized that androgens synthesized intracellularly
by fibroblasts can influence the production of collagen and elastic
fibers in the stroma.
An unexpected finding was the localization of type 5 17ß-HSD and
3ß-HSD in blood vessel walls, including the endothelial cells. This
observation, however, correlates well with recent findings from this
laboratory indicating the presence of types 1 and 2 5-reductase mRNA
in blood vessel walls in human prostate and skin (33). Recently, we
have also observed that immunoreactive type 5 17ß-HSD is present in
the blood vessel walls in other tissues, such as skin, breast, uterus,
and ovary (Pelletier et al., unpublished data). The role of
the steroidogenic intracrine enzymes in these vascular structures is
unknown.
Previously, it has been shown that ARs were present in vascular smooth
muscle and endothelial cells of human skin (65, 66). Bergh and Damber
(67) found that nuclear ARs were present in the muscular layer of
almost all arteries within the rat testis. These authors have suggested
that testicular blood vessels could be a target organ for androgens and
may mediate some of the effects of androgens on testicular
microcirculation. Furthermore, in the developing human prostate,
Aumuller et al. (68) found that AR was positive in the
nuclei of vascular smooth muscle and endothelial cells. Because ARs are
present in the endothelial cells, smooth muscle cells, and fibroblasts
of blood vessels (Table 1), it may be speculated that locally
biosynthesized androgens are exerting a paracrine and/or intracrine
action in blood vessels. It is also possible that these androgens are,
up to an unknown extent, released into the blood circulation, to reach
some target tissues, although their global impact is likely to be
minimal. Interestingly, Franck-Lissbrant et al. (69) have
shown that, in the rat prostate, testosterone could induce a rapid
response of the vasculature that precedes growth of the glandular
epithelium. It might well be that cells of the blood vessels are
stimulated by locally made androgens, to produce paracrine growth
factors, which could promote the growth of the secretory epithelium.
Further studies are required to elucidate the role of the steroids
synthesized by cells of the blood vessel walls. The present data
clearly indicate new mechanisms of androgen formation, which may play
an important role, not only in normal human prostate physiology but
also in the pathogenesis of BPH and possibly prostate cancer.
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Acknowledgments |
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Received July 7, 1998.
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 J. Simard, M.-L. Ricketts, S. Gingras, P. Soucy, F. A. Feltus, and M. H. Melner Molecular Biology of the 3{beta}-Hydroxysteroid Dehydrogenase/{Delta}5-{Delta}4 Isomerase Gene Family Endocr. Rev., June 1, 2005; 26(4): 525 - 582. [Abstract] [Full Text] [PDF]
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D M Peehl Primary cell cultures as models of prostate cancer development Endocr. Relat. Cancer, March 1, 2005; 12(1): 19 - 47. [Abstract] [Full Text] [PDF]
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J. T. Arnold, H. Le, K. K. McFann, and M. R. Blackman Comparative effects of DHEA vs. testosterone, dihydrotestosterone, and estradiol on proliferation and gene expression in human LNCaP prostate cancer cells Am J Physiol Endocrinol Metab, March 1, 2005; 288(3): E573 - E584. [Abstract] [Full Text] [PDF]
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 M. Quinkler, B. Sinha, J. W Tomlinson, I. J Bujalska, P. M Stewart, and W. Arlt Androgen generation in adipose tissue in women with simple obesity - a site-specific role for 17{beta}-hydroxysteroid dehydrogenase type 5 J. Endocrinol., November 1, 2004; 183(2): 331 - 342. [Abstract] [Full Text] [PDF]
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G. Pelletier, V. Luu-The, S. Li, J. Ouellet, and F. Labrie Cellular Localization of mRNA Expression of Enzymes Involved in the Formation and Inactivation of Hormonal Steroids in the Mouse Prostate J. Histochem. Cytochem., October 1, 2004; 52(10): 1351 - 1356. [Abstract] [Full Text] [PDF]
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W. Qiu, M. Zhou, F. Labrie, and S.-X. Lin Crystal Structures of the Multispecific 17{beta}-Hydroxysteroid Dehydrogenase Type 5: Critical Androgen Regulation in Human Peripheral Tissues Mol. Endocrinol., July 1, 2004; 18(7): 1798 - 1807. [Abstract] [Full Text] [PDF]
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 I. Franck Lissbrant, E. Lissbrant, A. Persson, J.-E. Damber, and A. Bergh Endothelial Cell Proliferation in Male Reproductive Organs of Adult Rat Is High and Regulated by Testicular Factors Biol Reprod, April 1, 2003; 68(4): 1107 - 1111. [Abstract] [Full Text] [PDF]
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G. Pelletier Effects of Estradiol on Prostate Epithelial Cells in the Castrated Rat J. Histochem. Cytochem., November 1, 2002; 50(11): 1517 - 1524. [Abstract] [Full Text] [PDF]
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B.-l. Chang, S. L. Zheng, G. A. Hawkins, S. D. Isaacs, K. E. Wiley, A. Turner, J. D. Carpten, E. R. Bleecker, P. C. Walsh, J. M. Trent, et al. Joint Effect of HSD3B1 and HSD3B2 Genes Is Associated with Hereditary and Sporadic Prostate Cancer Susceptibility Cancer Res., March 1, 2002; 62(6): 1784 - 1789. [Abstract] [Full Text] [PDF]
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T. Suzuki, A. D. Darnel, J.-I. Akahira, N. Ariga, S. Ogawa, C. Kaneko, J. Takeyama, T. Moriya, and H. Sasano 5{{alpha}}-Reductases in Human Breast Carcinoma: Possible Modulator of in Situ Androgenic Actions J. Clin. Endocrinol. Metab., May 1, 2001; 86(5): 2250 - 2257. [Abstract] [Full Text]
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O. Barbier, H. Lapointe, M. El Alfy, D. W. Hum, and A. Bélanger Cellular Localization of Uridine Diphosphoglucuronosyltransferase 2B Enzymes in the Human Prostate by in Situ Hybridization and Immunohistochemistry J. Clin. Endocrinol. Metab., December 1, 2000; 85(12): 4819 - 4826. [Abstract] [Full Text]
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New Insight into the Molecular Basis of 3{beta}-Hydroxysteroid Dehydrogenase Deficiency: Identification of Eight Mutations in the HSD3B2 Gene in Eleven Patients from Seven New Families and Comparison of the Functional Properties of Twenty-Five Mutant Enzymes J. Clin. Endocrinol. Metab., December 1, 1999; 84(12): 4410 - 4425. [Abstract] [Full Text]
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G. Pelletier, V. Luu-The, A. Charbonneau, and F. Labrie Cellular Localization of Estrogen Receptor Beta Messenger Ribonucleic Acid in Cynomolgus Monkey Reproductive Organs Biol Reprod, November 1, 1999; 61(5): 1249 - 1255. [Abstract] [Full Text]
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S. Gingras and J. Simard Induction of 3{beta}-Hydroxysteroid Dehydrogenase/ Isomerase Type 1 Expression by Interleukin-4 in Human Normal Prostate Epithelial Cells, Immortalized Keratinocytes, Colon, and Cervix Cancer Cell Lines Endocrinology, October 1, 1999; 140(10): 4573 - 4584. [Abstract] [Full Text]
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