All lobes are responsive to both estrogens and to androgens, but to varying degrees; the VP is more sensitive to androgens and the AP more sensitive to estrogens [159, 165]. In rat prostate, both testosterone and estrogen have been shown to regulate the level of the long PRL receptor mRNAs in a tissue-specific manner [92]. In addition to steroid hormones, several different growth factors and other pituitary hormones have been shown to regulate cellular growth, differentiation and apoptosis.
A
CTION OF ANDROGENS IN THE PROSTATEAndrogen is a critical factor for the survival of prostatic epithelial cells.
Underdeveloped prostate gland is seen in eunuchs who lack androgen stimulation since childhood [166]. Castration-induced androgen-withdrawal
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regress the the number of epithelial cells in the prostate gland via an active process of apoptosis [167, 168]. Apoptosis can be observed within one day after castration and nearly 2/3 of epithelial cells are lost in the VP by seven days of castration [169]. In contrast, testosterone replacement to castrated rats stimulates the re-growth of the gland to its normal size via proliferation of new epithelial cells from basal cells [170].
I
NTERACTIONS BETWEEN PROLACTIN AND ANDROGENS IN THE PROSTATE GLANDPRL has been shown to potentiate the action of androgens in the support and stimulation of prostatic growth and metabolism [171-173]. This has been hypothezised to be accomplished through increasing prostate receptivity to androgens, mainly by affecting AR levels and 5-alpha reductase activity.
Results suggest that PRL is involved in regulating AR synthesis, at least partially by direct action on the prostate gland. In immature, hypophysectomized male rats, PRL treatment can significantly increase AR mRNA levels [174]. Findings in adult, castrated and pituitary grafted rats suggest that PRL promotes LP growth via an increase in nuclear AR levels, and thus optimizes tissue response to circulating testosterone [175].
Furthermore, pituitary grafting in immature rats can produce a significant increase in the weight of the seminal vesicles and the VP and AP [176]. In the VP, nuclear AR content increased, whereas the cytosolic AR content decreased, suggesting increased translocation of the AR to the nucleus. In a study on human BPH patients, cytosolic and nuclear levels of AR were shown to be proportional to plasma PRL levels [177]. These findings indicate plasma PRL involvement in the regulation of AR content also in the benign human prostate.
Recently the existence of crosstalk between the signal transduction systems of steroid hormones and peptide hormones/growth factors were recognized [178-180] which provides a mechanism for locally produced growth factor influence on AR activation. In the progression of prostate cancer to an androgen-independent state, local growth factors, such as PRL, may prove instrumental in regulation of cell growth.
In rat, hyperprolactinemia by pituitary grafting can lead to increased 5-alpha reductase activity in the testis [181] but indications of a PRL-induced increase in 5-alpha reductase activity in the prostate is limited [182]. PRL mediation of steroid uptake through alterations of the plasma membrane permeability in human BPH tissue has also been reported [183].
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To interpret findings in rodent versus human studies, one needs to be aware of the important differences in influence of PRL on circulating androgen levels.
In man, PRL is known to decrease circulating androgen levels through depression of gonadotrophine release from the pituitary gland [184], whereas in rodents, PRL can elevate circulating androgen levels by increasing the response to luteinizing hormone in the testis [185].
A
CTION OF ESTROGENS IN THE PROSTATEA hierarchy of estrogen responsiveness in the three prostatic lobes has been revealed in male mice, with the AP being the most responsive, the dorsolateral lobe less responsive, and the ventral lobe the least responsive.
[159].
The expression of both known estrogen receptor subtypes in adult human and rodent prostate is now well established, with expression of ERα described primarily in a subset of stromal cells and ERβ restricted to the ductal epithelium [186-188]. Although the newly discovered ERβ shares many of the functional characteristics of ERα, the molecular mechanisms regulating the transcriptional activity of ERβ may be distinct from those of ERα. For example, the growth effects of estrogens during fetal development are mediated primarily by ERβ in the human prostate, which can be immunodetected in the nuclei of nearly 100% of epithelial and in the majority of stromal cells throughout gestation. However, ERα has been shown to contributes to postnatal glandular development [156].
Estrogen plays an important role both in prostate physiology and pathophysiology. The developing prostate is particularly sensitive to estrogenic exposure. During prostate morphogenesis, elevated levels of endogenous (maternal or excess local production) or exogenous (diethylstilbestrol or environmental chemicals) estrogens induce permanent changes in prostate growth in rodents. Fetal and neonatal exposure to estrogens results in pathological and functional changes of the prostate [189].
High-dose of testosterone together with estradiol stimulates prostatic carcinogenesis in adult male rats [190]. In mice, these effects are dose-related as low-dose estrogen exposure may increase the adult prostate size whereas high-dose exposure reduces prostate size [189]. An increase in AR levels has been associated with low-dose estrogen-induced increases in prostate size [190]. Neonatal exposure of rodents to high doses of estrogen is known to permanently imprint the growth and function of the prostate and predispose the gland to hyperplasia and severe dysplasia analogous to PIN with aging [160]. Following neonatal exposure of rats to high doses of
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estrogen on days 1-5 of life, a permanent reduction in prostate growth and responsiveness to androgen occurs relative to a reduction in AR expression in adult animals [165]. Moreover, exogenous estrogen administration in adult rodents leads to squamous metaplasia of the AP [157, 159]. As mentioned earlier, development of squamous metaplasia has been shown to be mediated through stromal ERα [160, 161].
I
NTERACTIONS BETWEEN PROLACTIN AND ESTROGENS IN THE PROSTATE GLANDEstrogen are known to act directly on pituitary lactotrophs and indirectly on the hypothalamic dopaminergic system and several studies suggest that neonatal estrogen treatment can induce long-term alterations in pituitary synthesis and release of PRL [191-193]. Moreover, estrogens are well-known to promote PRL release resulting in elevated PRL levels systemically [78, 79]. It is thus quite possible that the prostate effects of estrogen imprinting are in fact partially PRL-mediated. Furthermore, PRL is able to stimulate expression of both ERα and ERβ in corpus luteum and decidua during pregnancy [194-196] as well as stimulate estradiol binding activity or mRNA levels in the mammary gland [197] and liver [198]. In the prostate, effects of estrogen treatment appear to be in part mediated by increased PRL levels [199], something that is further demonstrated in the aforementioned dysplastic prostate model of estrogen-treated Noble rats [142].
A
CTION OF OTHER PEPTIDE HORMONES AND GROWTH FACTORS IN THE PROSTATEGrowth factors regulate cellular growth, differentiation and apoptosis. In addition to steroid hormones, an array of positive and negative growth factors controls the balance between cell proliferation and apoptosis in the prostate. Several oncogene products that contribute to neoplastic proliferation have been found to be homologues to growth factors, growth factor receptors, or molecules in the signal-transducing pathways of these receptors. There are numerous growth factor families that have been implicated in normal, neoplastic and malignant prostate growth and it is far beyond this thesis to review the action of all reported hormones and growth factors. The in the literature mentioned growth factors include, the IGF family, EGF, TGF, FGF family, platelet-derived growth factor (PDGF) and VEGF, which all are the main stimulatory regulators of proliferation in the prostate [200]. Furthermore, the pituitary hormones, GH and luteinizing
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hormone (LH), play physiologically significant roles in the normal prostate, either alone or synergistically with androgens [201]. Nevertheless, the involvement of these hormones in the development of BPH and prostatic carcinoma is an issue that needs to be addressed.
The TGF-family is the main inhibitory regulator of proliferation acting on the epithelial cells. However, recent studies have demonstrated proliferative and anti-apoptotic effects of TGFβ in stromal cells [202].
Altogether, the growth factors exert autocrine and paracrine effects upon stromal and epithelial cells and interact with other factors and binding proteins to control prostate growth [203].