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Department of Anatomy and Medicity Research Laboratory, Institute of Biomedicine, University of Turku, 20520 Turku, Finland and Department of Laboratory Medicine, Tumor Biology, Lund University, 205 02 Malmö, Sweden
Address all correspondence and requests for reprints to: Pirkko Härkönen, Institute of Biomedicine, Department of Anatomy and Medicity Research Laboratory, University of Turku, FI-20520 Turku, Finland. E-mail: harkonen{at}utu.fi.
Prolactin (PRL) has long been known to influence prostate as one of its numerous targets and multiple effects (1, 2, 3). The early in vivo experiments showed the regressive effects of hypophysectomy (4) and the capacity of pituitary grafts (5) to support prostate growth in castrated animals. PRL was recognized as a major effective component of the pituitary extract and numerous in vivo experiments exploiting classical endocrine ablation and replacement techniques and use of inhibitors strongly suggested that PRL has an androgen (A) independent on growth and differentiated functions of the prostate (1, 2). Hyperprolactinemia caused by different reasons invariably caused prostatic hyperplasia and stromal accumulation of inflammatory cells (1, 2, 6). The in vitro experiments using cultured prostate explants (7, 8, 9) and cell lines (10) confirmed that exogenous PRL is able to stimulate proliferation and secretion (7, 8) and to increase survival (9) of prostatic epithelium. Detailed studies on the prostatic signaling pathways of PRL have demonstrated expression of PRL receptors (PRLR; Refs. 11, 12, 13) and coupling of the receptor activation mainly to the Jak2-Stat5a/b pathway but also to the ras-MAPK pathway (14, 15).
Through the years, accumulating experimental evidence demonstrating the prostatic stimulation by pituitary or exogenously added PRL have inspired several clinical studies on the possible correlations between hyperprolactinemia and prostatic growth disorders (16, 17) and on the possible therapeutic effects of pharmacological lowering of serum PRL level. So far those studies have not, however, provided consistent conclusions on the role for pituitary PRL in human prostatic disease (18, 19) or even in normal prostatic function.
The demonstration of expression PRL itself in rat and human prostatic epithelium (8, 20) made the picture even more complicated. Furthermore, prostate as several other tissues is able to process PRL protein by posttranslational glycosylation, phosphorylation, or proteolytic cleavage (21, 22) to molecular derivatives, which have different cellular targets and biological activities, which considerably adds to the complexity of putative PRL actions (22). The in vivo and in vitro experiments have demonstrated that the level of locally produced prostatic PRL is regulated by A (20). Considering the fact that in prostate cultures many of the effects of exogenous PRL were similar to those of A it was hypothesized that PRL mediates some of A actions, but so far the functions of the locally produced prostatic PRL have not been known.
The recent application of gene-modulated animal models have provided a new insight into the functional role and significance of PRL action in various target tissues. Somewhat surprisingly, disruption of either PRL (23) or PRLR gene (24) did not cause major prostatic changes. In PRLR null mice, the lack of major structural changes suggests that the embryonal and pubertal development of prostate is not dependent on PRLR-mediated actions. The decreased prostatic weight in PRL-deficient mice does suggest, however, that PRL has a role in maintaining adult prostate (25). In addition, fertilization capacity of male PRLR null mice was decreased although the spermatogenesis was functioning (24), which suggests that the production of optimal seminal fluid composition by prostate and other accessory sex glands is disturbed. The proper secretory function of adult prostate would thus be maintained by PRLR-mediated mechanisms.
In contrast to rather slight phenotypic changes in the knockout mice transgenic mice overexpressing PRL under a universal metallothionein (Mt) promoter presented a very clear prostatic phenotype with a considerable enlargement and hyperplasia of the gland (26). The Mt-PRL transgenic model represents the condition of pituitary-derived hyperprolactinemia, and it is associated with increased serum levels of A. The model thus confirmed previous experimental evidence for hyperprolactinemia-induced prostatic growth (1, 2, 6, 27), but it could not fully differentiate between the effects of PRL and A. The Mt-PRL transgenic model did not provide any answers as to the putative role of local prostatic PRL, either.
This is now done with the new transgenic mouse model [probasin (Pb)-PRL] presented by Kindblom et al. (2003) in this issue (28). The Pb-PRL model eventually proves that increased prostatic PRL is able to lead to important biological consequences. In this mouse line, PRL gene expression is targeted to prostate with a prostate-specific Pb promoter (29) without noticeable systemic effects such as increased serum level of PRL or A. The effects are most interesting. They include stromal expansion, accumulation of inflammatory cells, ductal dilatation, and focal epithelial dysplasias, which all are considered basic characteristics of human benign prostatic hyperplasia (BPH; Ref. 30).
Several mechanistic questions arise. Does local prostatic PRL influence both epithelium and stroma? Is the effect direct or indirect? (See Fig. 1
.) In prostate, PRLRs are primarily expressed in epithelial cells (8, 11, 13), in which the major immunohistochemical reaction is localized to the apical surface of the cells. This localization would allow a direct autocrine and paracrine stimulation of epithelium but the classical signaling route through the basolateral membrane domain may still be possible. There are also reports on stromal expression of prostatic PRLR (11). The mechanisms by which PRL could be intracellularly sorted to gain access to such receptors or other cellular destinations are not presently known. Furthermore, posttranslational processing and proteolytic cleavage of PRL (22) may produce secondary signaling molecules with altered characteristics and cellular targets as exemplified by antiangiogenic 16K PRL (22). PRL may also stimulate stromal and epithelial compartments by inducing synthesis of secondary mediators.
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reductase activity (31), and AR expression (28, 32). In tissue cultures, the prostatic responses to A and PRL were largely similar (stimulation of proliferation and expression of secretory proteins, increased survival), but there was one important difference: the capacity of maintaining the epithelial integrity (7, 8). In the presence of A, the epithelium of human and rat prostate was regular and polarized, whereas in the presence of PRL the epithelium showed proliferative and disorganized morphology very much resembling the focal epithelial dysplasias presented in PRL transgenic mice (26, 28). When both PRL and A were included, the epithelium was stimulated but organized. Malignant tumors have not been seen in hyperprolactinemic or PRL overexpressing transgenic models but one might predict that an accidental escape of PRL expressing epithelial cells from A control might seriously predispose them to development and progression of epithelial atypias. In this context, it is of interest that bromocriptine, an inhibitor of PRL release is able to protect against development of prostatic dysplasias under certain conditions (33). Also, an analog of phosphorylated PRL (an antagonist of PRLR) was able to decrease tumorigenesis and growth of PRL expressing human prostate cancer cells in nude mice (34). All these observations support the concept that excessive PRL predisposes prostatic epithelium to development of dysplastic changes and may facilitate transforming events. The major remaining question is whether (increased) prostatic PRL is associated with development of human BPH. Elevated levels of PRL (35) and expression of PRLRs (13) have been reported in hyperplastic human prostate, but there are little data on the role of prostatic PRL in the development of BPH. Based on the experimental results provided by Kindblom et al. (28) obtaining such data should, however, be of major interest. Future studies on the pathways and regulation of prostate-derived PRL will hopefully provide new approaches and specific tools for the analysis and therapeutic exploitation of the complex endocrinology and paracrinology of PRL in prostrate.
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Received March 24, 2003.
Accepted for publication March 26, 2003.
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  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]
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 A. Bartke Prolactin in the Male: 25 Years Later J Androl, September 1, 2004; 25(5): 661 - 666. [Full Text] [PDF]
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