1 Laboratoire de Physiologie Cellulaire, Institut National de la Santé et de la Recherche Médicale (INSERM) EPI-9938, 3 Laboratoire de Biologie du Développement, and 8 Laboratoire de Neuroendocrinologie du Développement, Université des Sciences et Technologies de Lille, 59655 Villeneuve d'Ascq; 2 Service d'Anatomo-pathologie, Centre Hospitalier de Roubaix, 59056 Roubaix; 4 Laboratoire de Neuroendocrinologie et de Physiopathologie neuronale, INSERM U422, 59045 Lille; 5 Laboratoire Pierre Fabre, La Chartreuse, and 6 Laboratoire Pierre Fabre Médicaments, 81106 Castres; and 7 Université Pierre et Marie Curie, 75006 Paris, France
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ABSTRACT |
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The effects of the polypeptide hormone
prolactin (PRL) in the development and regulation of benign prostate
hyperplasia (BPH) and also in prostate cancer are not very well
characterized. This study examines the action of PRL, either alone or
in association with androgens [testosterone (T) or dihydrotestosterone
(DHT)], in the rat prostate gland. The effects of PRL and androgens
were investigated after 30 and 60 days in control, castrated, castrated with a substitutive implant of T or DHT, and sham-operated Wistar rats.
To enhance PRL release, we induced hyperprolactinemia by administering
chronic injections of sulpiride (40 mg · kg1 · day
1). Chronic
hyperprolactinemia induces enlargement and inflammation of the lateral
rat prostate without any histological changes on ventral and dorsal
lobes. We also demonstrate that hyperprolactinemia induces Bcl-2
overexpression in the lateral rat prostate and that this could inhibit
the level of apoptosis. The in vivo model established here is a useful
in vivo approach for studying the hormonal regulation of normal and
pathological prostate development.
prolactin; testosterone; dihydrotestosterone
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INTRODUCTION |
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THE CONSTANT INCREASE IN LIFE EXPECTANCY has enhanced the incidence of benign prostate hyperplasia (BPH) and prostate cancer. In particular, prostate cancer is the second cause of male cancer-related death in the Western world (67).
It has now been clearly established that the growth, differentiation (16, 20, 64), and programmed cell death (22) of prostate cells are regulated by androgens. For this reason, the main treatment for prostate tumors consists of inhibiting cell growth by suppressing the action or production of endogenous androgens (6). However, despite this treatment, almost all tumors, and especially malignant tumors, continue to progress. The background of this clinical phenomenon is poorly understood. It has become obvious that other nonandrogenic factors, such as peptide hormones (1, 12, 56) and growth factors (17), are involved in prostate cell growth regulation.
Prolactin (PRL) is one of the nonsteroidal factors assumed to be involved in the proliferation of prostate cells (9) and in the development and regulation of BPH and prostate cancer (24, 25, 37, 39).
PRL levels increase with age (17, 62) whereas testosterone levels decrease (10, 36), indicating that the role of PRL in the development of prostate hyperplasia becomes increasingly important with age. Using organ cultures, Nevalainen et al. (39) showed that PRL induces differentiation and proliferation in rat and human prostate. These PRL actions are mediated through the signal transduction pathways triggered by both the short and long forms of PRL receptors. Furthermore, these authors showed that rat prostatic epithelial cells express prolactin, and they demonstrated an overall distribution of prolactin mRNA in the dorsal and lateral prostate (37). Other groups have suggested that PRL promotes the growth and proliferation of prostate cells in synergism with androgens (49). It has also been proposed that PRL could increase free steroid concentrations in the blood, as well as the uptake of testosterone (T) in prostate cells (14). On the other hand, it has also been suggested that PRL has an independent action on prostatic growth and metabolism (48, 52, 58). Some in vitro models of the prostate have been developed to investigate these problems, but an analysis of the independent and combined in vivo actions of these hormones is lacking. The importance of PRL was also shown by a study of PRL-transgenic mice (66), demonstrating a dramatic prostate enlargement.
In a recent study, we demonstrated that hyperprolactinemia induced a lateral rat prostate hyperplasia (60). We induced hyperprolactinemia by daily injections of 40 mg/kg of sulpiride, an antagonist of the type 2 dopamine receptor (D2), a mediator of dopamine-induced inhibition of PRL secretion (11, 35). In the present study, using the same in vivo model, we investigate the effects of hyperprolactinemia alone or in association with androgens [T or dihydrotestosterone (DHT)] on the different lobes of rat prostate gland. The lateral lobe was more sensitive to an increase in plasma PRL levels than the ventral and dorsal lobes. The hyperprolactinemia induced enlargement and inflammation of the lateral rat prostate without any histological changes on ventral and dorsal lobes. We also demonstrated that PRL may inhibit lateral lobe epithelial cell apoptosis by overexpressing Bcl-2.
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MATERIALS AND METHODS |
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Animals. One hundred and ten male Wistar rats (200-220 g) from Iffa Credo, France, were used. These animals were conditioned for 1 wk before experimentation. Rats were randomized and housed five per cage on a 12:12-h light-dark cycle. They were provided ad libitum with water and a standard laboratory chow.
During this work, all animal studies were conducted in accordance with the European Community's Council ruling of 24 November 1986 (86/609/EEC).Surgical procedures. All surgeries were performed on day 1 under ether anesthesia and strict sanitized conditions. The operated animals were treated with antibiotics (penicillin) to prevent infections.
Castrations were performed on day 1 via scrotal route by removing epididymal fat pads with the testes. The sham-castrated rats were opened, and their testes were dissected but not removed. Operated animals were then sutured, and the injured areas were disinfected with betadine solution and sprayed with aluspray (Vetoquinol). To add the desired quantity of exogenous androgens for comparison with control animals, we implanted Silastic medical-grade silicone tubing (1 cm length, 0.078 ID × 0.125 OD; Dow Corning, Midland, MI) filled with either T (Sigma) or DHT (Sigma) subcutaneously over the scapula. One end of the tubing was sealed with adhesive (Silastic Medical Adhesive; Dow Corning). After loading with the hormone, the unsealed end was sealed with adhesive. After the adhesive had hardened, the implants were put overnight in distilled water. The implants were inserted on day 8 in pockets formed over the dorsal area of the scapula. The incised area was disinfected and then sutured.Hyperprolactinemia induction. Hyperprolactinemia was induced by daily intraperitoneal injections of a 40 mg/kg aqueous sulpiride solution (± sulpiride, Sigma). Control animals were intraperitoneally injected daily with the carrier alone (NaCl 0.9%).
Another experimental approach was used to induce hyperprolactinemia: Alzet 2ML4 osmotic pumps delivering 2.5 µl/h of PRL (0.173 mg/ml) were implanted for 1 mo by use of the same surgical procedure as described above.Sampling.
Table 1 gives the surgical event
(castrations, sham castrations, and implants) and treatment (daily ip
injections of sulpiride or NaCl 0.9%) schedule for the various
experimental groups.
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Hormonal assays. Plasma levels of PRL and luteinizing hormone (LH) were measured by RIA with materials supplied by the National Institute of Diabetes and Digestive and Kidney Diseases rat pituitary hormone distribution program (Torrance, CA), with rat RP3-PRL and rat RP3-LH as reference preparations. T and DHT levels were measured by RIA with a TRK 600 kit (Amersham) according to a protocol from the manufacturer.
Histology. Tissue pieces were fixed in 10% neutral buffered formalin and embedded in paraffin. Histological analysis was performed on serial sections obtained from prostatic samples stained by hematoxylin-erythrosin-saffron.
Bcl-2 labeling. Immediately after dissection of the lateral prostate, pieces of ~1 mm × 1 mm were fixed by immersion in paraformaldehyde (1.5% in PBS) for 1.5 h at 4°C. After several washes (the final wash lasted all night), the blocks were infused for the next 24 h in a mixture of sucrose (2.5 M) and polyvinyl pyrrolidone (20%) and then frozen in liquid nitrogen. Sections (0.2 µm) were cut and positioned on glass slides. The sections were blocked with 1.2% gelatin in PBS (PBSG) for 30 min to avoid nonspecific binding and were subsequently incubated overnight at 4°C in 100% humidity with the primary antibodies for Bcl-2 (polyclonal rabbit IgG and AB-2 from Oncogene Research Products, Cambridge, MA). After several washes in PBSG, the slides were incubated for 1 h at 37°C with secondary antibodies (donkey anti-rabbit IgG labeled with FITC), washed in PBS, and mounted in Mowiol. The sections were observed under a Zeiss Axiophot microscope equipped with epifluorescence (excitation: 450-490 nm, emission: 520 nm). Negative controls consisted of omission of the primary antibody.
Western analysis. The cells or the tissues were disrupted in a Kontes glass tissue grinder fitted with a tight pestle. After centrifugation (10,000 g), the pellets were fractionated in a standard SDS-PAGE gel (15%) (29). After electrophoresis was complete, the proteins were transferred onto a nitrocellulose membrane by use of a semi-dry electroblotter (Bio-Rad). After the transfer was complete, the membrane was cut into thin strips that were further processed for Western blot. The strips were blocked for 1 h at room temperature in TNT (15 mM Tris buffer, pH 8, 140 mM NaCl, 0.05% Tween 20, and 5% nonfat dry milk), washed in TNT (3 times), and then soaked in primary antibodies (1 µM/ml in TNT): rabbit polyclonal antibody for the rat tissues (AB-2 from Oncogene Research Products), mouse monoclonal antibody for the cells (Sc-509 from Santa Cruz Biotechnology, Santa Cruz, CA), and rabbit polyclonal anti-actin (Sigma), for 1 h at room temperature. After thorough washes in TNT, the strips were transferred to the corresponding horseradish peroxidase-linked secondary antibodies (Zymed Laboratories, San Francisco, CA) diluted in TNT (1/7,500) for 1 h. After several washes in TNT without milk, the strips were processed for chemiluminescent detection using Supersignal West Pico chemiluminescent substrate (Pierce Chemical, Rockford, IL) according to the manufacturer's instructions. The blots were then exposed to X-Omat AR films (Eastman Kodak, Rochester, NY).
Statistical analysis. We expressed prostate weight relative to body weight (54). Variations in both prostate weight and plasma hormone levels were studied. Tukey's test was used to establish significant differences. Significance was established at levels of P < 0.05, P < 0.01, and P < 0.001.
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RESULTS |
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Hormonal assays: induction of chronic hyperprolactinemia in rats treated by sulpiride. We measured PRL, T, DHT, and LH levels from blood plasma of rats.
Sulpiride induced a rise in basal plasma PRL levels in all groups of animals treated (Table 2). It enhanced the basal PRL level by a factor of 6.2 under control conditions and 3.6 in castrated animals. In castrated DHT-implanted rats, sulpiride injections increased the basal PRL level by a factor of 12. Because previous reports (13, 15, 23) indicated an increase of PRL during stress, sham-castrated and solvent-injected groups were also evaluated. It had previously been shown that empty tubing implants had no effect on rat prostate growth (42, 53, 54). PRL levels in solvent-injected animals were not significantly different from those in controls (data not shown).
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Effects of hyperprolactinemia on the wet weight of prostate lobes. The wet weight of the prostate was examined when the animals were killed after 30 and 60 days of treatment with sulpiride, respectively. Because rat prostate is divided into three parts: the ventral lobe (VP), the lateral lobe (LP), and the dorsal lobe (DP), we show the different results obtained for each lobe.
Figure 1 illustrates the wet weight of the LP after 30 days of sulpiride treatment under various experimental conditions. In castrated and implanted animals, T and DHT induced an increase in the wet weight of the lateral lobe by factors of 3.8 and 5.1, respectively, compared with castrated rats.
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Induction of glandular hyperplasia of LP in sulpiride-treated rats. Similar histological aspects were observed after 30 and 60 days of experimentation. Sulpiride had no effect on VP and DP morphology.
The LP of normal (Fig. 4A), sham-castrated, and solvent-injected rats (data not shown) was most frequently composed of the same proportion of small and large glands, both limited by columnar epithelial cells. The LPs of castrated rats without any substitutive treatment presented atrophy with a large majority of small glands (Fig. 4B). The LP atrophy of castrated animals receiving a substitutive treatment with T (Fig. 4C) or with DHT (data not shown) was particularly attenuated compared with LP of sham-castrated rats (Fig. 4B).
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Overexpression of Bcl-2 in the LP of control and sulpiride-treated
rats.
The control LP sections showed a spotted cytoplasmic labeling
(organelles, except the nucleus) on the whole of epithelial cells (Fig.
5A). In control and
sulpiride-treated LP, the labeling was intensified in the epithelial
cells bordering the acini, giving target-like images that
become brighter at the periphery of the acini (Fig.
5B). The infiltrated cells were only faintly labeled. In the
VP, the labeling observed under control and control sulpiride-treated conditions was similar to that shown in the control LP sections (data
not shown).
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DISCUSSION |
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In this study we demonstrate the effects of chronic hyperprolactinemia on rat prostate growth. A particularly significant alteration in the rats with chronic hyperprolactinemia was a dramatic enlargement of the LP. This LP hyperplasia was focally associated with acute, chronic inflammation.
To induce a chronic hyperprolactinemia, we used a model of long-term (30 and 60 days) androgen treatment associated with daily sulpiride injections. Sulpiride, a specific D2 inhibitor, is known to stimulate PRL secretion from the pituitary (11, 35). It also has two actions on PRL plasma levels: sulpiride initially induces a peak of prolactinemia in ~30 min (26 times the initial value), followed by a gradual reduction in PRL levels. After 2 h of treatment, PRL levels remain higher (6 times the basal level) than the initial value before injection. Thus, a chronic (60-day) treatment with sulpiride causes a significant increase in plasma PRL level (62.54 ± 26.77 ng/ml) compared with control (10.16 ± 2.57 ng/ml) or solvent-injected (18.9 ± 9.03 ng/ml) animals. In our experiments, the rats were killed on the day after the last sulpiride injection, so the prolactinemia measured does not represent the PRL peak, but rather the chronic PRL level after 60 days of treatment with sulpiride.
Our experiments in castrated-adrenalectomized rats show that the contribution of the adrenals to endogenous androgen level support is negligible. Thus the adrenals do not interfere with rat prostate growth. These results are in agreement with van Weerden et al. (61): these authors measured a very low level of androstenedione and no detectable plasma concentrations of dehydroepiandrosterone in rat adrenal gland cell suspensions. On the contrary, in humans, the adrenals significantly contribute to the control of the androgen level (34).
In a previous work (60), we demonstrated that hyperprolactinemia induced rat LP enlargement. In the present study we characterize one of the possible mechanisms of action of PRL on the prostate: the overexpression of Bcl-2. The effects of hypeprolactinemia were observed only in the LP of the rat prostate, affecting wet weight, histological structure, and Bcl-2 expression. The VP and DP were insensitive to the rise in PRL and did not show any Bcl-2 overexpression. The LP is considered the most hormone-sensitive part of the prostate (30, 54, 55). It has been shown that the dorsolateral lobes are the parts of the rat prostate that give rise to spontaneous and experimental tumors (45-47) with varied hormone responsiveness. Moreover, the rat LP and DP are considered to be the most homologous to the human prostate (48). Furthermore, it has been suggested that PRL plays an important role in BHP and human prostate cancer development (24, 25, 37, 39).
Hyperprolactinemia, stimulated by daily sulpiride injections, induced a marked enlargement of the LP in noncastrated animals (4.1 times control after 30 days and 2 times control after 60 days). PRL had no effect on castrated animals. However, in castrated, T-implanted, and castrated DHT-implanted rats, the rise in PRL levels also increased the weight of the LP (by a factor of 2.4 for T and 1.6 for DHT, respectively, after 30 days and by a factor of 3 for T and 3.2 for DHT, respectively, after 60 days), suggesting that PRL acts in synergy with the androgens.
In our experiments, 1-cm T implants partially restored (45%) normal T
level. Robaire et al. (53) showed that 2.5-cm T implants are
needed to restore the physiological T level in the rat. However, 1-cm
DHT implants increased the DHT level by 336% compared with the
physiological level in noncastrated rats. This difference in T and DHT
level of recovery by use of 1-cm implants is explained by the fact that
the physiological level of DHT (formed by 5-reductase from T) was
lower (0.183 ± 0.032 ng/ml) than the T level (2.087 ± 0.272 ng/ml).
The T level was higher in noninjected rats than in animals treated with sulpiride (Table 2). Because it has been shown that hyperprolactinemia decreases the number of pituitary gonadotropin-releasing hormone receptors and LH secretion (4, 8), the T level, controlled by LH, is therefore also reduced. Thus, in our experiments, the rise in wet weight of the LP in the noncastrated sulpiride-injected animals could be explained by the rise in PRL level.
In men, the PRL level increases (17, 62) and the T level diminishes with age (10, 36). Some research has demonstrated the same changes in rat PRL (8) and T (4) levels. In our study, in castrated T-implanted groups, the T level was 55% less than control. We used 1-cm T implants, which deliver one-half a physiological T level, to mimic the T level of aging rats. In our study, the hyperprolactinemia induced by sulpiride produced LP hyperplasia. Thus, in old rats and in aging men, a rise in prolactinemia could be sufficient to induce prostate hyperplasia, even with lower T levels. In this in vivo model, it is possible to develop a hormonal environment similar to that of aging rats and elderly men.
Our histological studies demonstrate that hyperprolactinemia induces
glandular hyperplasia in the LP, but not the DP and VP, in the rats
with increased PRL levels. An increase was observed in the proportion
of large glands associated with inflammation. This was not the case in
the LP of animals not injected with sulpiride. Robinette
(54) reported that estradiol-17 had a specific action on LP growth. Estradiol-17
causes inflammation in dorsolateral (30) and lateral rat prostates (59) that can
be reduced by treatment with bromocriptine (a dopaminergic agonist
known to decrease PRL levels). Thus the potent involvement of
estradiol-17
in prostate dysplasia and inflammation implies PRL
action. Moreover, an enlargement of the dorsolateral prostate was shown
(66) in transgenic mice with an overexpressed PRL
receptor, suggesting the implication of PRL in the growth of the
prostate gland.
The mechanism by which PRL affects prostate growth is not yet known. In our study we noticed synergistic effects between PRL and androgens. This phenomenon could be due to the fact that PRL enhances the T effect (14), as well as increasing cytosol and nuclear androgen receptor levels in rats (49). Furthermore, androgens (40, 49) and PRL (49, 50) upregulate PRL receptor levels in the rat prostate. Moreover, hyperprolactinemia induces the turnover of tissue DHT content in the LP (5, 50, 55). Some in vitro studies have demonstrated an independent action of PRL in prostate cells (48, 52, 58). PRL also has an androgeno-independent proliferative effect in the rat LP in organ culture (31). PRL receptors have been identified in the VP (43), as well as in both LP and DP rat and human prostates (39). Some of these receptors are located on the basal and lateral surfaces of the epithelial cells (39). These receptors may fix circulatory PRL and induce the growth of the LP in rats. Nevertheless, PRL receptors are also located on the apical surfaces of the secretory epithelial cells of prostatic acini (39). Because the epithelial prostatic cells are joined by tight junctions, PRL receptors located on the apical surface of these cells are not accessible to circulatory PRL, unlike basolateral cell membrane receptors. However, in recent experiments, Nevalainen and colleagues (37, 39) clearly demonstrated that prostatic epithelial cells were able to produce PRL. They used in situ hybridization to show that the epithelium of rat DP and LP expressed PRL mRNA and protein. Thus prostatic PRL may act in an autocrine/paracrine manner in the prostate through apical receptors, where it may mediate some androgen actions. The incidence of serum hyperprolactinemia on prostatic PRL synthesis is unknown.
Interestingly, the experiments carried out by Nevalainen et al. (37) demonstrated that the expression pattern of PRL protein was different in the DP and LP. In the DP, the cytoplasm of sparsely located, single epithelial cells was very strongly stained. In contrast, in the LP, the majority of the epithelial cells were stained, but the staining was less intense than in the DP. These results probably explain the fact that, in our experiments, we did not observe the effect of PRL on the DP.
In addition, for the first time, we observed a rise in the expression of the antiapoptotic protein Bcl-2 in the LP epithelial cells of noncastrated animals treated with sulpiride. We did not notice this phenomenon either in the VP or in the DP. Bcl-2 is known to downregulate apoptosis in prostate cells (7, 28, 44, 51), as in other models (19, 21, 63, 65). Bcl-2 also provides resistance to androgen depletion in androgen-sensitive human prostate cancer cells LNCaP (51). Thus, in this in vivo model of hyperprolactinemia, the overexpression of Bcl-2 in noncastrated animals led to a decrease in the apoptosis level in the epithelial cells of the LP. This modifies the balance between proliferation and apoptosis, eventually causing the LP hyperplasia shown in the histological study. In the NB2 rat lymphoma cell line, PRL induced a 15-fold increase in the level of Bcl-2 mRNA within 3 h (32). The authors suggest that the trophic action of PRL results from suppression of cell death induced by the rise in the expression of Bcl-2 (27, 32). Recently, it was shown that PRL is a survival factor in LP epithelium in organ culture (2). In our study, the increase in weight of the LP may be explained by PRL-induced inhibition of apoptosis mediated by Bcl-2 overexpression. Furthermore, the tissue-specific modulation of Bcl-2 expression by PRL in the rat prostate may explain the lack of sensitivity of the VP to PRL, even if each rat prostate lobe has PRL receptors (3, 18, 26, 38). The antiapoptotic action of PRL on prostate cells requires further investigation and may be useful in developing a treatment.
In conclusion, the chronic hyperplasia model proposed in this work may serve as a useful approach for studying the development mechanism of prostate hyperplasia. This model, representing PRL-dependent hyperplasia, is probably close to the human pathology, where the implication of PRL is uncontested.
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ACKNOWLEDGEMENTS |
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We thank Ariane Bouteillier, Claudine Carbon, and Christelle Milluy for carrying out the histological technical procedures; Dr. Ralph Buttyan (New York, NY) for the gift of Bcl-2-transfected LNCaP cell line; National Institute of Diabetes and Digestive and Kidney Diseases and the National Hormone Pituitary Program (Torrance, CA) for the gift of PRL and LH materials; and Dr. Olga Zolle for reading this article.
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FOOTNOTES |
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* These authors contributed equally to this work.
This work was supported by grants from Pierre Fabre Médicaments, the Institut National de la Santé et de la Recherche Médicale, the Association pour la Recherche sur le Cancer, and the Ligue Nationale contre le Cancer (all of France).
Address for reprint requests and other correspondence: F. Van Coppenolle, Laboratoire de Physiologie Cellulaire, Centre de Biologie Cellulaire, USTL, INSERM EPI 9938, Bâtiment SN3, 59655 Villeneuve d'Ascq Cedex, France (E-mail: fvancopp{at}pop.univ-lille1.fr).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 5 May 2000; accepted in final form 6 September 2000.
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REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Abrahamsson, P,
Wadström L,
Alumets J,
Falkmer S,
and
Grimelius L.
Peptide-hormone and serotonin-immunoreactive cells in normal and hyperplastic prostate glands.
Path Res Pract
181:
675-683,
1986[ISI][Medline].
2.
Ahonen, T,
Harkonen P,
Laine J,
Rui H,
Martikainen P,
and
Nevalainen M.
Prolactin is a survival factor for androgen-deprived rat dorsal and lateral prostate epithelium in organ culture.
Endocrinology
140:
5412-5421,
1999
3.
Aragona, C,
and
Friesen H.
Specific prolactin binding sites in the prostate and testis of rats.
Endocrinology
97:
677-684,
1975[Abstract].
4.
Banerjee, P,
Banerjee S,
Lai J,
Strandberg J,
Zirkin B,
and
Brown T.
Age-dependent and lobe-specific spontaneous hyperplasia in the brown Norway rat prostate.
Biol Reprod
59:
1163-1170,
1998
5.
Blankenstein, M,
Bolt-de Vries J,
Coert A,
Nievelstein H,
and
Schroder F.
Effect of long-term hyperprolactinemia on the prolactin receptor content of the ventral prostate.
The Prostate
6:
277-283,
1985[Medline].
6.
Carraro, J,
Raynaud J,
Koch G,
Chisholm G,
Di Silverio F,
Teillac P,
Da Silva F,
Cauquil J,
Chopin D,
Hamdy F,
Hanus M,
Hauri D,
Kalinteris A,
Marencak J,
Perier A,
and
Perrin P.
Comparison of phytotherapy (Permixon) with finasteride in the treatment of benign prostate hyperplasia: a randomized international study of 1,098 patients.
The Prostate
29:
231-240,
1996[Medline].
7.
Colombel, M,
Vacherot F,
Diez S,
Fontaine E,
Buttyan R,
and
Chopin D.
Zonal variation of apoptosis and proliferation in the normal prostate and benign prostatic hyperplasia.
Br J Urol
82:
380-385,
1998[ISI][Medline].
8.
Console, G,
Gomez Dumm C,
Brown O,
Ferese C,
and
Goya R.
Sexual dimorphism in the age changes of the pituitary lactotrophs in rats.
Mech Aging Dev
95:
157-166,
1997[Medline].
9.
Costello, L,
and
Franklin R.
Effect of prolactin on the prostate.
The Prostate
24:
162-166,
1994[Medline].
10.
Davidson, J,
Chen J,
Crapo L,
Gray G,
Greenleaf W,
and
Catania J.
Hormonal changes and sexual function in aging men.
J Clin Endocrinol Metab
57:
71-77,
1983[Abstract].
11.
Debeljuk, L,
Rozados R,
Daskal H,
Velez V,
and
Mancini A.
Acute and chronic effects of sulpiride on serum prolactin and gonadotropin levels in castrated male rats (38581).
Proc Soc Biol Med
148:
550-552,
1975[Abstract].
12.
Di Sant'Agnese, P.
Neuroendocrine differentiation in carcinoma of the prostate. Diagnostic, prognostic, and therapeutic implications.
Cancer
70:
254-268,
1992[ISI][Medline].
13.
Donnerer, J,
and
Lembeck F.
Different control of the adrenocorticotropin-corticosterone response and of prolactin secretion during cold stress, anesthesia, surgery, and nicotine injection in the rat: involvement of capsaicin-sensitive sensory neurons.
Endocrinology
126:
921-926,
1990[Abstract].
14.
Farnsworth, W.
Prolactin effect on the permeability of human benign hyperplastic prostate to testosterone.
Prostate
12:
221-229,
1988[ISI][Medline].
15.
Fujikawa, T,
Soya H,
Yoshizato H,
Sakaguchi K,
Doh-Ura K,
Tanaka M,
and
Nakashima K.
Restraint stress enhances the gene expression of prolactin receptor long form at the choroid plexus.
Endocrinology
136:
5608-5613,
1995[Abstract].
16.
Geller J. Pathogenesis and pathological treatment of benign
prostatic hyperplasia. The Prostate Suppl: 95-104,
1989.
17.
Hammond, G,
Kontturi M,
Maattala P,
Puukka M,
and
Vihko R.
Serum FSH, LH and prolactin in normal males and patients with prostatic diseases.
Clin Endocrinol (Oxf)
7:
129-135,
1977[ISI][Medline].
18.
Hanlin, M,
and
Yount A.
Prolactin binding in the rat ventral prostate.
Endocr Res Commun
2:
489-502,
1975[ISI][Medline].
19.
Hayashi, R,
Luk H,
Horio D,
and
Dashwood R.
Inhibition of apoptosis in colon tumors induced in the rat by 2-amino-3-methylimidazo[4,5-f]quinoline.
Cancer Res
56:
4307-4310,
1996[Abstract].
20.
Horton, R.
Benign prostatic hyperplasia. New Insights.
J Clin Endocrinol Metab
74:
504A-504C,
1992[Medline].
21.
Ibrado, A,
Huang Y,
Fang G,
Liu L,
and
Bhalla K.
Overexpression of Bcl-2 and bcl-xL inhibits Ara-C-induced CPP323/Yama protease activity and apoptosis of human acute myelogenous leukemia HL-60 cells.
Cancer Res
56:
4743-4748,
1996[Abstract].
22.
Isaacs, J.
Antagonistic effect of androgen on prostatic cell death.
The Prostate
5:
545-557,
1984[Medline].
23.
Jahn, G,
and
Deis R.
Stress-induced prolactin release in female, male and androgenized rats: influence of progesterone treatment.
Endocrinology
110:
423-428,
1986.
24.
Janssen, T,
Kiss R,
and
Schulman C.
Organ culture of human tissue model of hormonal and pharmacological regulation of benign prostatic hyperplasia and of prostate cancer.
Acta Urol Belg
14:
7-14,
1995.
25.
Kadar, T,
Ben-David M,
Pontes J,
Fekete M,
and
Schally A.
Prolactin and luteinizing hormone receptors in human benign prostatic hyperplasia and prostate cancer.
The Prostate
12:
299-307,
1988[Medline].
26.
Kledzik, G,
Marshall S,
Campbell G,
Gelato M,
and
Meites J.
Effects of castration, testosterone, estradiol on specific prolactin-binding activity in ventral prostate of male rats.
Endocrinology
98:
373-379,
1976[Abstract].
27.
Krumenacker, J,
Buckley D,
Leff M,
McCormack J,
de Jong G,
Gout P,
Reed J,
Miyashita T,
Magnuson N,
and
Buckley A.
Prolactin-regulated apoptosis of Nb2 lymphoma cells: pim-1, Bcl-2, and Bax expression.
Endocrine
9:
163-170,
1998[ISI][Medline].
28.
Kyprianou, N,
Tu H,
and
Jacobs S.
Apoptotic versus proliferative activities in human benign prostatic hyperplasia.
Hum Pathol
27:
668-675,
1996[ISI][Medline].
29.
Laemmli, U.
Cleavage of structural proteins during the assembly of the head of bacteriophage T4.
Nature
227:
680-685,
1970[ISI][Medline].
30.
Lane, K,
Leav I,
Ziar J,
Bridges R,
Rand W,
and
Ho S.
Suppression of testosterone and estradiol-17-induced dysplasia in the dorsolateral prostate of Noble rats by bromocriptine.
Carcinogenesis
18:
1505-1510,
1997[Abstract].
31.
Lee, C,
Hopkins D,
and
Holland J.
Reduction in prostatic concentration of endogenous dihydrotestosterone in rats by hyperprolactinemia.
The Prostate
6:
361-367,
1985[Medline].
32.
Leff, M,
Buckley D,
Krumenacker J,
Reed J,
Miyashita T,
and
Buckley A.
Rapid modulation of the apoptosis regulatory genes, bcl-2 and bax, by prolactin in rat Nb2 lymphoma cells.
Endocrinology
137:
5456-5462,
1996[Abstract].
33.
Leung, L,
and
Wang T.
Differential effects of chemotherapeutic agents on the Bcl-2/Bax apoptosis pathway in human breast cancer cell line MCF-7.
Breast Cancer Res Treat
55:
73-83,
1999[ISI][Medline].
34.
Mason, J,
Bird I,
and
Rainey W.
Adrenal androgen biosynthesis with special attention to P450c17.
Ann NY Acad Sci
774:
47-58,
1995[Abstract].
35.
Nakagawa, K,
Obara T,
Matsubara M,
and
Kubo M.
Relationship of changes in serum concentrations of prolactin and testosterone during dopaminergic modulation in males.
Clin Endocrinol
17:
345-352,
1982[ISI][Medline].
36.
Nankin, H,
and
Calkins J.
Decrease bioavailable testosterone in aging normal and impotent men.
J Clin Endocrinol Metab
63:
1418-1420,
1986[Abstract].
37.
Nevalainen, M,
Valve E,
Ahonen T,
Yagi A,
Paranko J,
and
Harkonen P.
Androgen-dependent expression of prolactin in rat prostate epithelium in vivo and in organ culture.
FASEB J
11:
1297-1307,
1997
38.
Nevalainen, M,
Valve E,
Ingleton P,
and
Harkonen P.
Expression and hormone regulation of prolactin receptors in rat dorsal and lateral prostate.
Endocrinology
137:
3078-3088,
1996[Abstract].
39.
Nevalainen, M,
Valve E,
Ingleton P,
Nurmi M,
Martikainen P,
and
Harkonen P.
Prolactin and prolactin receptors are expressed and functioning in human prostate.
J Clin Invest
99:
618-627,
1997
40.
Nevalainen, M,
Valve E,
Makela S,
Blauer M,
Tuohimaa P,
and
Harkonen P.
Estrogen and prolactin regulation of rat dorsal and lateral prostate in organ culture.
Endocrinology
129:
612-622,
1991[Abstract].
41.
Niimi, M,
Takahara J,
and
Kawanishi K.
Plasma concentration of prolactin during four-day osmotic pump infusion of thyrotropin-releasing hormone and vasoactive intestinal polypeptide in rats.
Endocrinol Jpn
32:
929-932,
1985[Medline].
42.
Paubert-Braquet, M.
Effect of Serenoa repens extract (Permixon) on estradiol/testosterone-induced experimental prostate enlargment in th rat.
Pharmacol Res
34:
171-179,
1996[ISI][Medline].
43.
Perez-Villamil, B,
Bordiu E,
and
Puente-Cueva M.
Involvement of physiological prolactin levels in growth and prolactin receptor content of prostate glands and testes in developing male rats.
J Endocrinol
132:
449-459,
1992[Abstract].
44.
Perlman, H,
Zhang X,
Chen M,
Walsh K,
and
Buttyan R.
An elevated Bax/Bcl-2 ratio corresponds with the onset of prostate epithelial cell apoptosis.
Cell Death Diff
6:
48-54,
1999[ISI][Medline].
45.
Pollard, M.
The Lobund-Wistar rat model of prostate cancer.
J Cell Biochem Suppl
16H:
84-88,
1992.
46.
Pollard, M.
Dihydrotestosterone prevents spontaneous adenocarcinomas in the prostate-seminal vesicle in aging L-W rats.
The Prostate
36:
168-171,
1998[Medline].
47.
Pollard, M.
Lobund-Wistar rat model of prostate cancer in man.
The Prostate
37:
1-4,
1998[Medline].
48.
Price, D.
Comparative aspects of development and structure in the prostate.
Natl Cancer Inst Monogr
12:
351-369,
1963.
49.
Prins, G.
Prolactin influence of cytosol and nuclear androgen receptors in the ventral, dorsal and lateral lobes of the rat prostate.
Endocrinology
120:
1457-1464,
1987[Abstract].
50.
Prins, G,
and
Lee C.
Influence of prolactin-producing pituitary grafts on the in vivo uptake, distribution and disappearance of [3H]testosterone and [3H]dihydrotestosterone by the rat prostate lobes.
Endocrinology
110:
920-925,
1982[ISI][Medline].
51.
Raffo, J,
Perlman H,
Chen M,
Day M,
Streitman J,
and
Buttyan R.
Overexpression of Bcl-2 protects prostate cancer cells from apoptosis in vitro and confers resistance to androgen depletion in vivo.
Cancer Res
55:
4438-4445,
1995[Abstract].
52.
Reiter, E,
Lardinois S,
Klug M,
Sente B,
Hennuy B,
Bruyninx M,
Closset J,
and
Hennen G.
Androgen-independent effects of prolactin on the different lobes of the immature rat prostate.
Mol Cell Endocrinol
112:
113-122,
1995[ISI][Medline].
53.
Robaire, B,
Ewing L,
Irby D,
and
Desjardins C.
Interactions of testosterone and estradiol-17 on the reproductive tract of the male rat.
Biol Reprod
21:
455-463,
1979[ISI][Medline].
54.
Robinette, C.
Sex-hormone-induced inflammation and fibromuscular proliferation in the rat lateral prostate.
The Prostate
12:
271-286,
1988[Medline].
55.
Schacht, M,
Niederberger C,
Garnett J,
Sensibar J,
Lee C,
and
Grayhack J.
A local direct effect of pituitary graft on growth of the lateral prostate in rats.
The Prostate
20:
51-58,
1992[Medline].
56.
Shah, G,
Rayford W,
Noble M,
Austenfeld M,
Weigel J,
Vamos S,
and
Mebust W.
Calcitonin stimulates growth of human prostate cancer cells through receptor mediated increase in cyclic 3',5'-monophosphate and cytoplasmic Ca2+ transients.
Endocrinology
134:
596-602,
1994[Abstract].
57.
Shirahama, T,
Sakakura C,
Sweeney E,
Ozawa M,
Takemoto M,
Nishiyama K,
Ohi Y,
and
Igarashi Y.
Sphingosine induces apoptosis in androgen-independent human prostatic carcinoma DU-145 cells by suppression of bcl-X(L) gene expression.
FEBS Lett
407:
97-100,
1997[ISI][Medline].
58.
Smith, C,
Assimos D,
Lee C,
and
Grayhack J.
Metabolic action of prolactin in regressing prostate: independent of androgen action.
Prostate
6:
49-59,
1985[ISI][Medline].
59.
Tangbanluekal, L,
and
Robinette C.
Prolactin mediates estradiol-induced inflammation in the lateral prostate of Wistar rats.
Endocrinology
132:
2407-2416,
1993[Abstract].
60.
Van Coppenolle, F,
Le Bourhis X,
Carpentier F,
Delaby G,
Cousse H,
Raynaud JP,
Dupouy JP,
and
Prevarskaya N.
Pharmacological effects of the lipidosterolic extract of serenoa repens [Permixon(R)] on rat prostate hyperplasia induced by hyperprolactinemia: comparison with finasteride.
Prostate
43:
49-58,
2000[ISI][Medline].
61.
Van Weerden, W,
Bierings H,
van Steenbrugge G,
de Jong F,
and
Schröder F.
Adrenal glands of mouse and rat do not synthesize androgens.
Life Sci
50:
857-861,
1992[ISI][Medline].
62.
Vekemans, M,
and
Robyn C.
Influence of age in serum prolactin levels in women and men.
Br Med J
4:
738-739,
1975[ISI][Medline].
63.
Wada, M,
Doi R,
Hosotani R,
Lee J,
Fujimoto K,
Koshiba T,
Miyamoto Y,
Fukuoka S,
and
Imamura M.
Expression of Bcl-2 and PCNA in duct cells after pancreatic duct ligation in rat.
Pancreas
15:
176-182,
1997[ISI][Medline].
64.
Walsh, P.
Benign prostatic hyperplasia: etiological considerations.
Prog Clin Biol Res
145:
1-25,
1984[Medline].
65.
Wei, H,
Wei W,
Bredesen D,
and
Perry D.
Bcl-2 protects against apoptosis in neural cell line caused by thapsigargininduced depletion of intracellular calcium stores.
J Neurochem
70:
2305-2314,
1998[ISI][Medline].
66.
Wennbo, H,
Kindblom J,
Isaksson O,
and
Tornell J.
Transgenic mice overexpressing the prolactin gene develop dramatic enlargement of the prostate gland.
Endocrinology
138:
4410-4415,
1997
67.
Woolf, S.
Screening for prostate cancer with prostate specific antigen. An examination of the evidence.
N Engl J Med
333:
1401-1405,
1995