| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Regular Articles |
From the Department of Pathology,*
Tufts University,
Schools of Medicine and Veterinary Medicine, Boston, Massachusetts, the
Department of Biology,
Tufts Unversity,
Medford, Massachusetts, the Department of
Pathology,
Beth Israel Deaconess Medical
Center, West Campus, Harvard Medical School, Boston, Massachusetts, and
the Department of Urology,§
Stanford Medical
Center, Stanford, California
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Indirect evidence of possible PRL involvement in the development of benign prostatic hyperplasia (BPH) and/or carcinoma has come from reports that circulating hormone levels were significantly higher in older men when compared with those found in younger males.3,12,13 Moreover, patients with prostate cancer have been reported to have higher levels of plasma PRL than did age-matched controls,3,12,13 and high affinity PRL binding sites have been detected in normal, BPH, and neoplastic human prostate.3,11,14
PRL, along with growth hormone, belongs to a superfamily of growth factors.15,16 The peptide hormone is known to have highly pleiotropic actions including those related to regulation of growth and differentiation. These broad range of effects are now known to be mediated by the prolactin receptors (PRLr) present in a large number of tissues including the human prostate.11,15-17 PRLrs are devoid of intrinsic enzymatic activity15,16 but are known to signal intracellularly via the JAK/STAT pathway, as well as the Ras/Raf/MAP kinase cascade.15,16 Three isoforms of PRLr (long, intermediate, and short forms), which differ in the lengths of their cytoplasmic domains, have been identified in rat tissues,15,16,18 but only the long and an analogous intermediate form of the receptor have been detected in human tissues.18 Interestingly, among the rat isoforms, both the long and intermediate forms are capable of transducing lactogenic as well as mitogenic signals.15,16,18,19 In contrast, the short form does not transduce differentiation signals but can signal cell growth in NIH 3T3 cells.20
As reported for cells in the breast, brain, placenta, and lymphoid cells,17 Nevalainen et al11 recently demonstrated that PRL is produced locally by secretory epithelia in organ cultures of the human prostate. These findings indicate that an intraprostatic as well as a pituitary source for PRL exists and together with PRLr constitute an autocrine/paracrine pathway which likely mediates local hormone effects on the gland. In the current study, we used immunohistochemistry and in situ hybridization to localize PRLr in the developing and adult human prostate and in hyperplastic, dysplastic (also termed prostatic intraepithelial neoplasia), and carcinomatous lesions of the gland. Our goals were to investigate whether this key component of PRL action is present during prostatic organogenesis and to determine whether its expression is altered in BPH, prostatic intraepithelial neoplasia lesions, and carcinoma. To our knowledge this is the first comprehensive morphological investigation of PRLr expression in the human prostate across a wide spectrum of normal and pathological states. Overall, our findings indicate that PRL likely influences the development of the human prostate and contributes to the maintenance of the adult gland. Our results also suggest that PRL plays a role in early carcinogenesis of the human prostate and that diminished PRLr expression in poorly differentiated cancers may reflect a progressive loss of responsiveness to the peptide hormone in populations of neoplastic cells.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The majority of specimens were selected from a pool of 40 radical prostatectomies done at Stanford Medical Center during the years 1994–1997. Patients ranged from 54 to 71 years of age. Specimens selected for study included 10 samples of lesion-free tissue from the peripheral, central, and transition zones,21 5 BPH specimens, 20 examples of dysplasia of varying grades of severity, and 18 examples of Gleason grades 3–4 carcinoma. The methods used for the collection, fixation, sample selection, and processing of these specimens are the same as previously described.22 In addition archival tissues obtained at autopsy from collections at the Department of Pathology at Tufts University were also studied. They included prostates from two fetuses at 29 and 34 weeks of gestation who died 1 and 7 days, respectively, after premature birth, 2 glands from neonates that were 3 hours old and 1 week of age, and one prostate from a prepubertal individual who was 11 years old.
In Situ Hybridization
The sense and antisense probes used in this study were generated from the H1/H2 human prolactin receptor clone23 which had been inserted into a pBlueScript vector. The entire 2556-bp sequence of the receptor was digested with the BamHI restriction enzyme to generate a 200-bp fragment which was subcloned into the BamHI site of the pBlueScript vector. The fragment is from the cytoplasmic domain of the long form of the human prolactin receptor, from nucleotides 1029 to 1233. This sequence was chosen because it has no homology with other members of the same family of receptors, such as the human growth hormone receptor.15,16,18 One microgram of the recombinant plasmid vector was linearized by Xbal and EcoRI enzymes to generate antisense and sense templates, respectively. To generate labeled riboprobes the templates were transcribed using RNA polymerases T7 (antisense) or T3 (sense), NTP labeling mix (the UTP component was 2/3 normal UTP, 1/3 digoxigenin -11 UTP), and RNase inhibitor. In vitro transcription was carried out at 37°C for 1 hour in a 1x transcription buffer (Boehringer Mannheim, Indianapolis, IN).
Formalin-fixed paraffin-embedded sections 5 µm thick were dewaxed, rehydrated, and washed in phosphate-buffered saline. In situ hybridization was carried out in an automated instrument (Gen II, Ventana Medical Systems, Tucson, AZ) in which all applications were standardized according to the manufacturer's protocols.
Briefly, the sections were exposed to proteinase K (100 µg/ml in 1 mol/L Tris-EDTA buffer, pH 8) for 8 minutes at 37°C. Prehybridization was carried out in 2x saline sodium citrate (SSC) for 15 minutes at 45°C. Sense or antisense riboprobes in 100 µl of hybridization buffer (50% deionized formamide, 2x SSC, 10% dextran sulfate, 1% SDS and 250 µg/ml denatured herring sperm DNA) were manually applied to the sections. Optimal dilutions of riboprobe in the hybridization buffer generally ranged from 1:100 to 1:300 (concentration: 10–20 pmol/L riboprobe). The Ventana Automated System utilizes a unique "liquid coverslip."
Following a 1-hour hybridization at 42°C, the automated sequence continued with posthybridization washes. The stringency conditions were determined by the duration, temperature, and concentration of the SSC solutions. The highest stringency we used in this study was 0.5x SSC for 20 minutes at 65°C. A blocking solution, which included normal sheep serum and tetramisol (Sigma), was then applied to the sections. This was followed by 20 minutes' exposure to primary antibody (anti-digoxin; Sigma) diluted 1:500 in normal sheep serum/Tris-NaCl buffer. The detection steps used 5 reagents supplied by the manufacturer (Ventana Blue kit). The slides were removed from the machine, stained with nuclear fast red (Rowley Biochemical Institute, Danvers, MA), dehydrated, and coverslipped.
Negative controls included sections incubated with the sense probe, pretreated with RNase A, or by omission of probe. Positive controls were surgical biopsy specimens of human breast.
Immunohistochemistry
For these studies we used a monoclonal antibody, B.6, raised against a membrane-enriched fraction of a metastatic human breast cancer line (MCF-7) (a generous gift from Dr. B.K. Vonderhaar, National Cancer Institute). The specificity of this reagent both in its binding characteristics and immunostaining of T47-D human breast cancer cells have been reported.24 In addition, we also used a rabbit polyclonal antibody directed against the complete extracellular domain of the human PRLr, which we termed the CL-AB (a generous gift from Dr. Charles Clevenger, University of Pennsylvania Medical School).
Six-micrometer-thick sections were dewaxed, placed in a 0.01 mol/L citrate buffer (pH 6), and then heated in a microwave oven at high power for 2 or 3 cycles at 5 minutes each. The B.6 antibody was then applied at a dilution of 1:250 and the polyclonal reagent at 1:100. Biotinylated horse anti-mouse or goat anti-rabbit were used as secondary antibodies with the B.6 and polyclonal antibodies, respectively. The remaining immmunohistochemical procedures were carried out as previously described.22 For all omission controls, nonimmune or preimmune sera of mouse or rabbit origin were substituted for the primary antibodies at the appropriate dilutions. In addition, we preincubated the polyclonal reagent with the immunizing peptide as a blocking control. The blocking peptide is a chimera between glutathione-S-transferase and the extracellular domain of the human PRLr expressed in Escherichia coli (a gift from Dr. Charles Clevenger). Five µg of the peptide was incubated with 5 µl of the antibody overnight at 4°C and then applied to the sections. In addition, the specificity of the CL-AB for identifying PRLr in human prostate epithelium was determined by immunoblotting using the prostatic carcinoma cell lines LNCaP and PC-3 (see below). Positive controls were the same surgical biopsy specimens of human breast used for in situ hybridization studies.
The intensity of signal at both the mRNA and protein levels were independently evaluated and semiquantitated using a grading scale of 1–4, with 4 representing the highest value, by three of us (I.L., F.M., and M.L.).
Immunoblot
LNCaP, PC-3, and MCF-7 cell lines (American Type Culture Collection) were grown in RPMI 1640 medium, F-12 nutrient mixture (HAM) culture medium, and Dulbecco's modified Eagle's (high glucose) culture medium, respectively, supplemented with 10% heat-inactivated fetal bovine serum and 1% antibiotic-antimycotic (Gibco BRL, Gaithersburg, MD) at 37°C in a humidified atmosphere of 5% carbon dioxide and 95% air.
Approximately 1 x 106 cells were trypsinized, washed with phosphate-buffered saline, and protein lysates were extracted with lysis buffer (10% sucrose, 1% Nonidet P-40, 20 mmol/L Tris, pH 8.0, 137 mmol/L NaCl, 10% glycerol, 2 mmol/L EDTA, 10 mmol/L NaF, 1 mmol/L phenylmethylsulfonyl fluoride, and 1 µg of leupeptin) agitated on ice every 10 minutes for 30 minutes, and centrifuged for 20 minutes at 14,000 rpm. The supernatant was removed and the concentration was determined with a spectrophotometer (Beckman DU 650) using the DC protein assay (BioRad, Hercules, CA).
Western blotting was performed using the Novex transfer system (Novex, San Diego, CA), 12% Tris-glycine pre-cast Novex gel, and HyBond ECL nitrocellulose membrane (Amersham Life Science, Cleveland, OH). Four hundred µg of lysate was transferred to the membrane, blocked in 5% milk in TBST for 1 hour, and blotted overnight at 40°C with the CL-AB (1:3000 dilution in 5% milk). For detection, the membrane was incubated in horseradish peroxidase-steptavidin goat anti-rabbit secondary antibody (BioRad) (1:10000 dilution in 5% milk in TBST for 30 minutes at room temperature) and developed with the ECL detection system (Amersham).
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
As previously described,22
the fetal human prostate at
29–34 weeks of gestation is composed of immature stroma containing
branching cords of epithelial cells, some of which are arranged in
solid nests and others containing lumens (Figure 1, A and B)
. In that study, we used high
molecular weight cytokeratin immunostaining to show that solid
epithelial nests were entirely composed of basal cells.22
With lumen formation basal cells were located along the perimeters of
developing acini and ducts, a location found in the postnatal,
prepubertal, and adult prostate glands.22
|
. Faint
signals (<1) were also detected in the stroma (Figure 1A)
.
The immunolocalization of receptor protein in fetal, postnatal, and
prepubertal prostates was identical to that found at the message level.
Light intensity immunostaining (1–2+) for the receptor was detected in
the cytoplasm of both immature luminal and basal cells in these glands
(Figure 1B)
. Thus, when compared with transcript signals staining
intensity was reduced in these tissues regardless of whether the
B.6 or CL-AB antibody reagent was used (Figure 1B)
. Stromal staining
was rarely seen in these glands and when it was found it was always
faint (<1).
Normal Adult Prostate
Localization of PRLr mRNA was evident in all but one of the 25
adult prostate specimens we selected for in situ
hybridization studies. In all instances hybridization signals were
predominately found in the cytoplasm of epithelial cells and
approximated the levels of expression intensity found in immature
glands (1–2+) (Figure 1C)
. As was seen in the immature prostates, only
a very faint signal was present in the stromal compartment, where it
was exclusively localized in the cytoplasm of smooth muscle cells. No
consistent differences in either the intensity or in the localization
of PRLr mRNA expression was evident between the three anatomical zones
of the adult gland (1–2+).
In concert with these findings, the intensity of immunostaining in
these three zones mirrored results seen at the message level (Figure 1, D and E)
. Differences were, however, evident in the localization of
receptor staining with the two antibodies. Although both antibodies
localized the receptor predominately in the cytoplasm of epithelial
cells, the nuclei of basal cells were consistently stained with the
CL-AB antibody, a feature less frequently found in secretory cells
(Figure 1E)
. In contrast clear immunostaining of nuclei was not well
delineated with the B.6 reagent. Light staining of smooth muscle cells
(<1) was occasionally observed with the B.6 antibody, which rarely
occurred when the CL-AB reagent was used.
Benign Prostatic Hyperplasia
In the 5 cases of BPH studied we found that PRLr message and
protein were predominately localized in epithelial cells and that
signal intensities at both levels were comparable to what we observed
in normal prostate cells (see above and Figure 2, A and B
). As was the case for normal
prostatic epithelia, nuclear immunostaining with the CL-AB also
occurred in hyperplastic cells. In all BPH lesions, stromal expression
of the receptor approximated the faint intensity seen in normal
prostate tissue.
|
With rare exception (2 lesions in 2 separate cases) PRLr
expression was markedly increased (4+) in dysplastic epithelia when
compared with normal adult glandular cells (Figure 3, A–C, E, and F)
. This finding was
consistent at both the mRNA (Figure 3, A–C)
and protein levels (Figure 3, E and F)
. The enhanced (4+) expression was observed with each
antibody reagent and occurred irrespective of the grade of the
dysplastic lesion (Figure 3, E and F)
. Interestingly, unlike the
situation in epithelia found in normal and hyperplastic glands, the
nuclei of dysplastic cells were rarely stained by either antibody
reagent (Figure 3, E and F)
.
|
. In contrast, although the
intensity of expression in the majority of grade 4 carcinomas was
judged to be similar to that found in grade 3 cancers, the higher grade
lesions were commonly heterogeneous and contained foci of cells in
which the both the intensity of receptor mRNA signals and
immunostaining was diminished (<1+) (Figure 4, B and D)
. Hybridization
with the sense probe was consistently negative or greatly reduced when
compared with its antisense counterpart in all tissues studied (Figure 3D)
.
|
. Strong signals (3+) were
always detected in epithelial cells of the breast by in situ
hybridization or by immunohistochemistry with either antibody; all
staining was abolished when the control procedures listed above were
used.
Our immunoblot studies confirmed the specificity of the CL-AB for the
human prolactin receptor and yield important findings. Thus, the CL-AB
detected a strong major band of approximately 85–90 kd in lysates of
MCF-7, LNCaP, and PC-3 (Figure 5)
, which
is consistent with the size reported for the long form of the prolactin
receptor in the human breast.18,24
As expected, among the
three cell lines studied, the band staining strongest was detected in
lysates of MCF-7 cells which are derived from a carcinoma of the
breast, followed by LNCaP and PC-3 cells, respectively. Of particular
interest was the finding that the androgen-dependent LNCaP prostate
carcinoma cells yielded a significantly stronger-stained band for the
receptor when compared to that observed in lysates of the
androgen-independent PC-3 cells.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
In our study of both fetal and adult glands the receptor was
predominately expressed in epithelial cells. PRLr message and protein
were also detected in smooth muscle, albeit signal intensity at both
levels was always much less than that observed in epithelia. Receptor
transcript and protein were consistently present in the cytoplasm of
epithelial cells, but nuclear immunostaining was, however, also evident
with the CL-AB reagent. The clear nuclear immunostaining we found with
the CL-AB versus the B.6 reagent may be due to subtle
differences in epitopes recognized by the two antibodies. In this
regard the CL-AB reagent is directed against the complete extracellular
domain of PRLr and may therefore recognize specific epitopes that are
less precisely identified by the B.6 antibody which was produced
against whole membranes. While the significance of nuclear localization
for the receptor in the prostate is currently unclear, PRLr has been
identified in the nuclei other cells such as rat hepatocytes and Nb-2
lymphocytes.25-26
In the case of Nb-2 cells, the
action of interleukin-2 induces PRL translocation to the nucleus where
it causes the up-regulation of genes involved in the cells entry into S
phase.25
In this context, it is of interest to note the
consistent nuclear localization of PRLr in prostatic basal
cells,27
the major proliferative cell type in the normal
prostate,28
and the purported precursor of secretory
glandular epithelia.29
Because androgen receptor protein is
not immunodetectable in prostatic basal cells22,30
our
findings may indicate that PRLr, along with other peptide growth
factors,22,31,32
are involved in mediating the
proliferation of these precursor cells. We (I.L. and J.E.M.) had
previously localized epidermal growth factor receptor exclusively in
basal cells of the fetal human prostate, which, like its adult
counterpart, lacked immunohistochemically demonstrable androgen
receptor.22
We proposed that the localization of epidermal
growth factor receptor in fetal basal cells likely reflects a
developing paracrine relationship found later in adult glands between
these precursor cells and smooth muscle cells which express
transforming growth factor-
, the ligand for the
receptor.22
In contrast, the almost exclusive localization
of PRlr in both fetal basal and luminal cells suggest that
peptide-receptor interactions are restricted to the epithelial cell
compartment in the developing gland. In the adult prostate the presence
of the receptor in basal and secretory cells together with the reported
synthesis of PRL by the latter cells in organ culture11
is
consistent with an autocrine/paracrine pathway for the action of the
hormone within acinar/duct units of the prostate.
In our current study we found that the expression of PRLr appeared unchanged in BPH specimens when compared with normal glands. In contrast, markedly strong hybridization signals and immunostaining were evident in dysplastic epithelial cells irrespective of the grade of the lesion. Since dysplasia is a putative precursor of carcinoma,33,34 PRL action may therefore play an important role in early carcinogenesis of the gland. Support for this concept comes from both organ culture studies of human11 and rat35 prostate and from our in vivo studies in the Noble rat sex hormone-prostatic carcinoma model.36 The organ culture studies demonstrated that both rat and human prostate explants, supplemented with PRL, underwent proliferative changes that closely resembled cribriform dysplastic lesions found in the human gland.34 Moreover, using the Noble rat we (I.L. and S.M.H.) recently reported that the testosterone and estradiol-17ß treatment, used to induce prostatic dysplasia in this animal model,37 caused hyperprolactinemia and that the administration of bromocriptine blocked both the increase in circulating PRL and the development of the prostatic lesions.36 Results from the aforementioned studies taken together with our current findings in dysplastic human prostate lesions indicate that PRL may play a significant role in carcinogenesis of the gland as has been proposed for the rodent and human mammary gland.38,39 Moreover, the finding of an autocrine/paracrine pathway for localized PRL action in epithelial cells of human breast and prostate may explain past clinical findings in which inconsistencies in the association between hyperprolactinemia and carcinoma of both tissues have been reported.3,6,40
In addition to its possible enhancement of early prostatic carcinogenesis, diminished PRL responsiveness may also influence the progression of the neoplastic process. In this regard, we found that PRLr expression was heterogeneous and was often notably diminished in poorly differentiated foci within high grade carcinomas when compared with areas of lower grade cancer in the same neoplasm. Interestingly, the results of our immunoblot studies are consistent with the findings at the tissue level and support the concept that diminution of receptor expression is a feature of less differentiated prostatic carcinomas. In addition, results from a past study had shown that the growth of the transplantable, well differentiated, androgen-dependent rat prostatic carcinoma line R3327–3219 was significantly enhanced by pituitary graft-induced hyperprolactinemia.41 Moreover, the highest growth rates in this tumor line occurred when the hyperprolactinemic castrated rats were given testosterone. This was in marked contrast to the poorly differentiated androgen-independent subline 150, whose growth was unaffected by the hyperprolactinemic state. These investigators concluded that the enhanced growth of R3327–3219 in the testosterone-treated rats may have been due to the synergistic interaction between PRL and the androgen. Recent findings in transgenic mice by Wennbo et al42 support the concept that a synergistic interaction between androgen and PRL plays an important role in the pathogenesis of abnormal growth of the prostate. These workers reported that transgenic mice, which overexpress PRL and have elevated plasma levels of testosterone, consistently develop hyperplasia of the gland. PRL may however have a direct proliferative and differentiating effect on the gland that are independent of androgen action, as demonstrated by studies using organ cultures of the rat35 and human11 prostate, which were not supplemented with male hormones. In either case, the decreased expression of PRLr we observed in areas of poorly differentiated high grade carcinomas may reflect the emergence of cells that are no longer responsive to the action of PRL.
In summary, results from our current studies and those of Nevalainen et al,11 who have reported that PRL is locally produced by human prostate epithelium, suggests that the hormone is involved in modulating the normal growth, differentiation, and maintenance of the human prostate. Our findings of enhanced and diminished PRLr expression in dysplastic and poorly differentiated carcinomas respectively may indicate that the hormone plays a role in early carcinogenesis of the gland but that with progression, prostatic cancers become increasingly independent of its action. Finally, it should be noted that our investigation has focused only on the expression of the long form of the receptor and that the possibility exists that other isoforms of PRLr may be present in normal and diseased prostatic epithelia which may be involved in the pathogenesis of neoplasia in the gland.
|
Acknowledgements |
|---|
|
Footnotes |
|---|
Supported by National Institutes of Health Grants CA 15776 (to S.-M.H. and I.L.) and AG13965 (to S.-M.H.).
Accepted for publication December 2, 1998.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
and epidermal growth factor receptor in stromal and epithelial compartments of developing human prostate and hyperplastic, dysplastic, and carcinomatous lesions. Hum Pathol 1998, 29:668-675[Medline]
This article has been cited by other articles:
 |
|
 |
|
  S. N. Lauber and N. J. Gooderham The Cooked Meat Derived Genotoxic Carcinogen 2-Amino-3-Methylimidazo[4,5-b]Pyridine Has Potent Hormone-Like Activity: Mechanistic Support for a Role in Breast Cancer Cancer Res., October 1, 2007; 67(19): 9597 - 9602. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Goffin, S. Bernichtein, P. Touraine, and P. A. Kelly Development and Potential Clinical Uses of Human Prolactin Receptor Antagonists Endocr. Rev., May 1, 2005; 26(3): 400 - 422. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N Berteaux, S Lottin, E Adriaenssens, F Van Coppenolle, X Leroy, J Coll, T Dugimont, and J-J Curgy Hormonal regulation of H19 gene expression in prostate epithelial cells J. Endocrinol., October 1, 2004; 183(1): 69 - 78. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Li, T. J. Ahonen, K. Alanen, J. Xie, M. J. LeBaron, T. G. Pretlow, E. L. Ealley, Y. Zhang, M. Nurmi, B. Singh, et al. Activation of Signal Transducer and Activator of Transcription 5 in Human Prostate Cancer Is Associated with High Histological Grade Cancer Res., July 15, 2004; 64(14): 4774 - 4782. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. G. Robertson, J. Harris, M. J. Naylor, S. R. Oakes, J. Kindblom, K. Dillner, H. Wennbo, J. Tornell, P. A. Kelly, J. Green, et al. Prostate Development and Carcinogenesis in Prolactin Receptor Knockout Mice Endocrinology, July 1, 2003; 144(7): 3196 - 3205. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Harkonen Paracrine Prolactin May Cause Prostatic Problems Endocrinology, June 1, 2003; 144(6): 2266 - 2268. [Full Text] [PDF]
|
|
|
|
|
|
J. Kim, W. Luo, D.-T. Chen, K. Earley, J. Tunstead, L.-Y. Yu-Lee, and S.-H. Lin Antitumor Activity of the 16-kDa Prolactin Fragment in Prostate Cancer Cancer Res., January 15, 2003; 63(2): 386 - 393. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. A. Feldman, C. Longcope, C. A. Derby, C. B. Johannes, A. B. Araujo, A. D. Coviello, W. J. Bremner, and J. B. McKinlay Age Trends in the Level of Serum Testosterone and Other Hormones in Middle-Aged Men: Longitudinal Results from the Massachusetts Male Aging Study J. Clin. Endocrinol. Metab., February 1, 2002; 87(2): 589 - 598. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L.-Y. Yu-Lee Prolactin Modulation of Immune and Inflammatory Responses Recent Prog. Horm. Res., January 1, 2002; 57(1): 435 - 455. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. J. Ahonen, P. L. Harkonen, H. Rui, and M. T. Nevalainen PRL Signal Transduction in the Epithelial Compartment of Rat Prostate Maintained as Long-Term Organ Cultures in Vitro Endocrinology, January 1, 2002; 143(1): 228 - 238. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Untergasser, H. Rumpold, E. Plas, M. Witkowski, and P. Berger Seminal Plasma Factors Induce in Vitro PRL Secretion in Smooth Muscle Cells of the Human Prostate J. Clin. Endocrinol. Metab., November 1, 2001; 86(11): 5577 - 5584. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E. Taplin and S.-M. Ho The Endocrinology of Prostate Cancer J. Clin. Endocrinol. Metab., August 1, 2001; 86(8): 3467 - 3477. [Full Text] [PDF]
|
|
|
|
|
|
S. J. McPherson, H. Wang, M. E. Jones, J. Pedersen, T. P. Iismaa, N. Wreford, E. R. Simpson, and G. P. Risbridger Elevated Androgens and Prolactin in Aromatase-Deficient Mice Cause Enlargement, But Not Malignancy, of the Prostate Gland Endocrinology, June 1, 2001; 142(6): 2458 - 2467. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. B. Kline, H. Roehrs, and C. V. Clevenger Functional Characterization of the Intermediate Isoform of the Human Prolactin Receptor J. Biol. Chem., December 10, 1999; 274(50): 35461 - 35468. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. E. Stoker, C. L. Robinette, B. H. Britt, S. C. Laws, and R. L. Cooper Prepubertal Exposure to Compounds That Increase Prolactin Secretion in the Male Rat: Effects on the Adult Prostate Biol Reprod, December 1, 1999; 61(6): 1636 - 1643. [Abstract] [Full Text]
|
|
|
|
|
|
J. B. Kline and C. V. Clevenger Identification and Characterization of the Prolactin-binding Protein in Human Serum and Milk J. Biol. Chem., June 29, 2001; 276(27): 24760 - 24766. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
