Both androgens and estrogens play a significant role in the prostate and are critical for normal prostate growth and development. The role of androgens in the prostate and in prostate disease is well known, however, the role for estrogens in the prostate and in prostate disease is complex and is still only just beginning to be appreciated. Our understanding of the role and action of estrogens in the prostate has advanced significantly recently due to important discoveries, including the discovery of a second estrogen receptor subtype (ER-beta), the detection of aromatase in the prostate, and the identification of rapid nongenomic estrogen signaling. We now know that estrogens are essential for normal tissue homeostasis within the prostate and that too little or too much leads to perturbation of the glands growth and the emergence of disease. We are also beginning to recognize the importance and differential roles of the estrogen receptors ER-alpha and ER-beta. Specifically, the activation of ER-alpha leads to aberrant proliferation, inflammation, and the development of premalignant lesions, while, in contrast, the activation of ER-beta is critical in prostatic stromal-epithelial cell signaling and mediating antiproliferative effects that balance the proliferative action of androgens on the epithelia. These data have established the importance and complexity of estrogen action. We now know that estrogens have the capacity to exert both beneficial and adverse effects in the prostate via ER-beta and ER-alpha, respectively. Based on this, the selective targeting of estrogen action may form the basis of new therapies for prostate disease.

The Dual, Opposing Roles of Estrogen in the Prostate

Neonatal exposure to estrogens permanently alters rat prostate growth and epithelial differentiation leading to prostatic dysplasia on aging. The effects are lobe-specific, with the greatest response observed in the ventral lobe. Recently, a novel estrogen receptor (ER) complementary DNA was cloned from the rat prostate and termed ER-beta (ER beta) due to its high homology with the classical ER alpha. The protein possesses high affinity for 17beta-estradiol, indicating that ER beta is an alternate molecule for mediating estrogenic effects. Importantly, ER beta messenger RNA (mRNA) was localized to rat prostatic epithelial cells, which contrasts with the stromal localization of ER alpha in the rat prostate. The present study was undertaken to determine the ontogeny of ER beta mRNA expression in the rat prostate lobes and to examine the effects of early estrogen exposure on prostatic ER beta expression. Male rat pups were given 25 microg estradiol or oil on days 1, 3, and 5; were killed on day 1, 3 (oils only), 6, 10, 30, or 90; and prostate lobes were frozen. Longitudinal sections were processed for in situ hybridization using an 35S-labeled antisense mRNA probe corresponding to a 400-bp EcoRI-AccI fragment in the 5' untranslated region of rat ER beta complementary DNA. Image analysis was used to quantitate silver grains. In addition, total RNA was isolated from the ventral prostate (VP) and used for semiquantitative RT-PCR. Results from in situ hybridization revealed that at birth, ER beta was equivalently expressed at low levels in both mesenchymal and epithelial cells in oil-treated rats. From day 1 onwards, expression in all stromal cells slowly and significantly declined, so that in the control adult prostate, stromal ER beta mRNA was slightly above background. In the oil-treated control rats, epithelial ER beta mRNA increased to moderate levels between days 6-10 in the VP and days 10-15 in the dorsal and lateral lobes as cells began differentiation and ducts lumenized. A further significant increase in ER beta message was observed at day 30, which indicates that full epithelial ER beta expression may require the completion of functional differentiation. By day 90, expression levels were maximal and similar between the lobes. RT-PCR substantiated this developmental increase in ER beta between days 1-90. Neonatal exposure to estrogens did not have an immediate effect on prostatic ER beta mRNA levels as determined by in situ hybridization and RT-PCR. However, the marked increase in epithelial cell expression at day 30 observed in the control VP was dampened in the VP of animals exposed neonatally to estrogens. By day 90, the VP of estrogenized rats possessed low ER beta message levels compared with the high expression in oil controls. In contrast, the dorsal and lateral lobes of neonatally estrogenized rats possessed high levels of ER beta mRNA at day 90, equivalent to controls. The present data demonstrate that ER beta mRNA expression in the rat prostate is developmentally regulated, and that neonatal estrogen can affect this expression in the adult VP. Because the effect of neonatal estrogens was not immediate, the data imply that early estrogen exposure may not directly autoregulate ER beta expression, and suggests that the adult effects on ER beta mRNA expression may be indirect. The differences in ER beta mRNA imprinting in the separate lobes may account for or reflect the lobe-specific neonatal estrogen imprints previously observed in the rat prostate.

/pdf/estrogen-receptor-beta-messenger-ribonucleic-acid-ontogeny-9zyyh8dn79.pdf

Estrogen receptor-beta messenger ribonucleic acid ontogeny in the prostate of normal and neonatally estrogenized rats.

Estrogen receptor beta in the prostate.

Neonatal estrogenization of the mouse with diethylstilbestrol resulted in time-of-exposure and dose-dependent inhibition of the growth of the prostatic lobes observed at the age of 2 mon. The critical time was the days 1-6 of postnatal life. In neonatally estrogenized (neoDES) mice, responses to 5 alpha-dihydrotestosterone in terms of nuclear 3H-thymidine labelling were altered concomitantly with the inhibition of growth and were in accordance with changes in the relative volumes of epithelium, glandular lumina, and interacinar stroma. Secondary estrogen treatment of neoDES mice with 17 beta-estradiol did not increase 3H-thymidine labelling in the prostate of control or neoDES mice. However, it induced squamous epithelial metaplasia in periurethral collecting ducts and proximal parts of coagulating glands of neoDES animals. In control mice only slight epithelial hyperplasia could be observed after similar treatment. Estrogen receptors, located immunocytochemically in nuclei of stromal cell, corresponded with the sites of increased estrogen sensitivity, observed as metaplastic transformation. When the neoDES animals aged, epithelial hyperplasia and dysplasia could be observed at distinct prostatic sites, ie, the periurethral collecting ducts and the coagulating glands and periurethral glands, and stromal inflammation become more extensive. Almost identical location of the epithelial changes and the altered estrogen response is suggestivemore » of causal relationship.« less

Regional differences in the prostate of the neonatally estrogenized mouse.

Diabetes mellitus of both type I (insulin-dependent) and type II (noninsulin-dependent) has adverse effects on male sexual and reproductive functions in adolescent boys and men, which include impairment of spermatogenesis, reduced sperm count, serum testosterone and seminal fluid volume, impotency, and loss of libido. Streptozotocin (STZ)-induced diabetes in rats provides a relevant model to study reproductive dysfunction under diabetic conditions, as they exhibit a number of deficits in reproductive function that resemble those seen in human diabetics. Therefore, the present investigation is aimed to understand the effects of STZ diabetes on the structure and development of ventral prostate during the critical period of sexual maturation in rats. Prepubertal (40-days-old) male Wistar rats were made diabetic by single injection of STZ (120 mg/kg body weight, intraperitoneally). Induction of diabetes was confirmed by serum insulin titer, hyperglycemia, and polyuria. To another set of STZ-diabetic rats, after 3 days of diabetes induction, insulin was replaced at a dose of 3 U/100 g body weight, subcutaneously in two equally divided doses at 8:00 AM and 6:00 PM. Diabetes caused regression of prostate, leading to a decrease in the absolute weight. Histologically, glandular epithelium has undergone shrinkage with transformation of acinar cells into low cuboidal type with less prominent secretory granules and blebs. Nevertheless, the secretory activity was not totally abolished. Interstitial space was increased due to shrinkage of glandular epithelium. Histomorphometric studies on the tubular diameter, volume and surface density of acinar epithelium, lumen, and stroma also support regressive changes in prostate. Insulin replacement prevented the detrimental effects of diabetes partially. These findings implicate the adverse effects of STZ diabetes on the differentiation of ventral prostate during sexual maturation.

Experimental diabetes has adverse effects on the differentiation of ventral prostate during sexual maturation of rats.

In a morphometric study on the ventral prostate and seminal vesicles in the rat, we investigated the changes in fibromuscular stroma, glandular epithelium, and glandular lumen. Animals were studied at 15, 30 and 45 days of age. The rapid prepubertal growth started earlier in the ventral prostate than in seminal vesicles. In addition, the effects of neonatal administration of estrogens on the different tissue compartments were studied, comparing rats that had been castrated and/or treated with estrogen at birth to intact animals at 15 days of age. Estrogens caused a decrease in the volume of the glandular epithelium and increased the volume of the fibromuscular stroma in both ventral prostate and seminal vesicles. Castration partially abolished the estrogen-induced growth of the stroma, which suggests that the growth is dependent on testicular factors. The difference in proportion of the fibromuscular stroma between the two glands is evidence that the size of the whole seminal vesicles has increased whereas the size of the ventral prostate has decreased.

M C Lucena

Papers

Morphometric analysis of the rat ventral prostate and seminal vesicles during prepubertal development: effects of neonatal treatment with estrogen.