Biomedical subjects

G S Prins

Publications and source records attributed to G S Prins.

At least 19 recordsLinked to original sources

PubMed2005

Neurodistribution of androgen receptor immunoreactivity in the male frog, Rana esculenta.

Sexual behavior in vertebrates depends on the cyclic release of steroids and their binding to the brain receptors. Previously, we demonstrated the presence of specific binding of (3)H-testosterone and staining with PG-21 in the brain of the adult male frog, Rana esculenta. Here, we report our further receptor characterization using an anti-androgen receptor antiserum, PG-21, and the androgen site of action in frog brain. Nuclei, which contained cells labeled for the androgen receptor (AR), were mainly identified in the olfactory bulbs, preoptic-septal region, infundibulum, amygdala, thalamus, tectum, torus semicircularis, and medulla. The neuroanatomical AR staining appears similar to that in other lower vertebrates.

Animals↗

PubMed2004

Abnormal morphology of the penis in male rats exposed neonatally to diethylstilbestrol is associated with altered profile of estrogen receptor-alpha protein, but not of androgen receptor protein: a developmental and immunocytochemical study.

Objectives of the study were to determine developmental changes in morphology and expression of androgen receptor (AR) and estrogen receptor (ER)alpha in the body of the rat penis exposed neonatally to diethylstilbestrol (DES). Male pups received DES at a dose of 10 microg per rat on alternate days from Postnatal Day 2 to Postnatal Day 12. Controls received olive oil vehicle only. Tissue samples were collected on Days 18 (prepuberty), 41 (puberty), and 120 (adult) of age. DES-induced abnormalities were evident at 18 days of age and included smaller, lighter, and thinner penis, loss of cavernous spaces and associated smooth muscle cells, and increased deposition of fat cells in the corpora cavernosa penis. Fat cells virtually filled the entire area of the corpora cavernosa at puberty and adulthood. Plasma testosterone (T) was reduced to an undetectable level, while LH was unaltered in all treated groups. AR-positive cells were ubiquitous and their profile (incidence and staining intensity) did not differ between control and treated rats of the respective age groups. Conversely, ERalpha-positive cells were limited to the stroma of corpus spongiosus in all age groups of both control and treated rats, but the expression in treated rats at 18 days was up-regulated in stromal cells of corpora cavernosa, coincident with the presence of morphological abnormalities. Hence, this study reports for the first time DES-induced developmental, morphological abnormalities in the body of the penis and suggests that these abnormalities may have resulted from decreased T and/or overexpression of ERalpha.

Aging↗

PubMed2001

Androgen receptor mediates the reduced tumor growth, enhanced androgen responsiveness, and selected target gene transactivation in a human prostate cancer cell line.

The growth and development of the prostate gland are regulated by the androgen and the androgen receptor (AR). Despite our molecular understanding of the roles of the AR regulating; a downstream target gene transcription, the direct or indirect (stromally mediated) actions of the androgen in controlling prostate cell growth and differentiation are still unclear. In this report, an invasive; and metastatic human prostate tumor cell line, androgen-repressed human prostate cancer cell line (ARCaP), either transduced with wild-type human AR (hAR) or a control neomycin-resistant plasmid DNA, was used to evaluate the direct role of AR in regulating prostate tumor cell growth and gene transcription. Results showed that: (a) introduction of wild-type hAR to ARCaP cells restored positive androgen regulation of prostate tumor cell growth in vitro through an enhanced cell-cycle progression from G(0)/G(1) to S and G(2)-M phases; (b) hAR was shown to transactivate glucocorticoid-responsive element but not prostate-specific antigen promoter-directed reporter gene expression; and (c) hAR-transduced ARCaP cells exhibited reduced growth, invasion, and migratory behavior in vitro and tumor growth in vivo. These results suggest that the introduction of hAR into the invasive human prostate cancer ARCaP cell line restored its androgen-regulated cell growth, decreased the rate of tumor growth, and selectively activated AR target gene expression. These cellular functions in response to androgen are commonly associated with increased differentiation of prostate epithelial cells.

Androgens↗

PubMed2001

Estrogen imprinting of the developing prostate gland is mediated through stromal estrogen receptor alpha: studies with alphaERKO and betaERKO mice.

Neonatal exposure of rodents to high doses of estrogen permanently imprints the growth and function of the prostate and predisposes this gland to hyperplasia and severe dysplasia analogous to prostatic intraepithelial neoplasia with aging. Because the rodent prostate gland expresses estrogen receptor (ER)-alpha within a subpopulation of stromal cells and ERbeta within epithelial cells, the present study was undertaken to determine the specific ER(s) involved in mediating prostatic developmental estrogenization. Wild-type (WT) mice, homozygous mutant ER (ERKO) alpha -/- mice, and betaERKO -/- mice were injected with 2 microg of diethylstilbestrol (DES) or oil (controls) on days 1, 3, and 5 of life. Reproductive tracts were excised on days 5 or 10 (prepubertal), day 30 (pubertal), day 90 (young adult), or with aging at 6, 12, and 18 months of age. Prostate complexes were microdissected and examined histologically for prostatic lesions and markers of estrogenization. Immunocytochemistry was used to examine expression of androgen receptor, ERalpha, ERbeta, cytokeratin 14 (basal cells), cytokeratin 18 (luminal cells), and dorsolateral protein over time in the treated mice. In WT-DES mice, developmental estrogenization of the prostate was observed at all of the time points as compared with WT-oil mice. These prostatic imprints included transient up-regulation of ERalpha, down-regulation of androgen receptor, decreased ERbeta levels in adult prostate epithelium, lack of DLP secretory protein, and a continuous layer of basal cells lining the ducts. With aging, epithelial dysplasia and inflammatory cell infiltrate were observed in the ventral and dorsolateral prostate lobes. In contrast, the prostates of alphaERKO mice exhibited no response to neonatal DES either immediately after exposure or throughout life up to 18 months of age. Furthermore, neonatal DES treatment of betaERKO mice resulted in a prostatic response similar to that observed in WT animals. The present findings indicate that ERalpha is the dominant ER form mediating the developmental estrogenization of the prostate gland. If epithelial ERbeta is involved in some component of estrogen imprinting, its role would be considered minor and would require the presence of ERalpha expression in the prostatic stromal cells.

Animals↗

PubMed2001

Testosterone protects cerebellar granule cells from oxidative stress-induced cell death through a receptor mediated mechanism.

It is known that steroid hormones can affect neuronal susceptibility to different types of insults, including oxidative stress. Using an in vitro/ex vivo model, we have previously shown that cerebellar granule cells prepared from neonatal rats treated with a single dose of testosterone are less vulnerable to oxidative stress-induced cell death, via a mechanism involving an upregulation of the cellular antioxidant defenses. Whether the testosterone protective action on cerebellar granule cells was direct or indirect remained to be clarified. Therefore, in this study we have investigated the effects of in vitro testosterone treatment, to see whether it also protects cerebellar granule cells from oxidative stress-induced damage. Cerebellar granule cells treated with 10(-6) M testosterone for 48 h were found less susceptible to damage induced by 50 microM hydrogen peroxide, as shown by a 30% decrease in the number of cells with apoptotic morphology. The addition of the androgen receptor antagonist flutamide abolished the protective effect of testosterone, suggesting an androgen receptor-mediated mechanism. This hypothesis was further supported by the presence of the androgen receptor in cultured cerebellar granule cells. The activity of the antioxidant enzyme catalase was also measured, and a 2-fold increase was detected in the testosterone treated cells, but not in the cells co-treated with flutamide. The present results demonstrate that cerebellar granule cells treated in vitro with testosterone are protected from oxidative stress via a mechanism mediated by the androgen receptor. Similarly to what we observed after in vivo administration of testosterone, the potentiation of the antioxidant defences seems to play a major role in the protection afforded by testosterone.

Androgen Antagonists↗

PubMed2001

Simultaneous determination of all-trans, 9-cis, 13-cis retinoic acid and retinol in rat prostate using liquid chromatography-mass spectrometry.

Since retinoic acid (RA) and RA receptors are key developmental regulators during organogenesis, they might participate in the abnormal development of the prostate caused by early estrogen exposure. In order to test this assumption, a sensitive analytical method that can differentiate 9-cis, 13-cis, and all-trans RA in small tissue samples ( approximately 8 mg) is required. Since retinol is the metabolic precursor to RA, simultaneous quantification of retinol would also provide valuable information. Here, we report a liquid chromatography-mass spectrometry method for simultaneous determination of retinol and 9-cis, 13-cis, and all-trans RA in rat prostate. Mass spectrometric signal responses for RA were compared using positive ion atmospheric-pressure chemical ionization (APCI) and electrospray, as well as positive ion and negative ion APCI. Positive ion APCI was selected for all subsequent analysis for its better sensitivity, and to provide simultaneous determination of retinol and RA. Ventral prostate tissue samples were homogenized and extracted following simple protein precipitation without derivatization. Baseline separation of 9-cis, 13-cis, and all-trans RA standards was obtained by using a non-porous silica C18 column. Selected ion monitoring of the ions m/z 301 and m/z 269 was carried out for mass spectrometric quantitative analysis. The ion of m/z 301 corresponded to the protonated molecule of RA, whereas the ion of m/z 269 corresponded to loss of water or acetic acid from the protonated molecule of retinol or the internal standard retinyl acetate respectively. The method has a linear response over a concentration range of at least three orders of magnitude. The limit of quantitation was determined to be 702 fmol all-trans RA injected on-column. The method showed excellent intra- and inter-assay reproducibility and good recovery, and is suitable for analyzing RA and retinol in small tissue samples (approximately 8 mg).

Alitretinoin↗

PubMed2001

Influence of neonatal estrogens on rat prostate development.

Brief exposure of rodents to estrogens during early development alters prostate branching morphogenesis and cellular differentiation in a dose-dependant manner. If estrogenic exposures are high, these disturbances lead to permanent imprints of the prostate, which include reduced growth, differentiation defects of the epithelial cells, altered secretory function and reduced responsiveness to androgens in adulthood. This process, referred to as neonatal imprinting or developmental estrogenization, is associated with an increased incidence of prostatic lesions with aging, which include hyperplasia, inflammation and dysplasia. To better understand how early estrogenic exposures can permanently alter prostate growth and function and predispose the gland to neoplasia, the effects of estrogens on prostatic steroid receptors, cell-cell communication molecules and key developmental genes were examined. Transient and permanent alterations in the expression of prostatic androgen receptors, estrogen receptors alpha (ERalpha) and beta, and retinoic acid receptors are observed. It is proposed that the estrogen-induced alterations in these critical transcription factors play a fundamental role in initiating prostatic growth and differentiation defects. Down-stream effects of the altered steroid receptor expression include disruption of TGFbeta paracrine communication, altered expression of gap junction connexin molecules and loss of epithelial cadherin on epithelial cells. Additionally, specific disruptions in the expression of prostatic developmental genes are observed in response to neonatal estrogen. An extended developmental period of hoxa-13 expression, a lack of hoxd-13 increase with maturation, and an immediate and sustained suppression of hoxb-13 was noted within prostatic tissue. A transient decrease in Nkx3.1 expression in the developing prostate was also observed. Thus subtle and overt alterations in Hox-13 and Nkx3.1 genes may be involved in the altered prostate phenotype in response to neonatal estrogen exposure. In summary, estrogen imprinting of the prostate gland is mediated through up-regulated levels of stromal ERalpha, which initiates alterations in steroid receptor expression within the developing gland. Rather than being an androgen-dominated process, as occurs normally, prostatic development is regulated by alternate steroids, including estrogens and retinoids, in the estrogenized animal. This, in turn, leads to disruptions in the coordinated expression of critical developmental genes including TGFbeta, Hox-13 genes and Nkx3.1. Since a precise temporal expression pattern of these and other molecules is normally required for appropriate differentiation of the prostatic epithelium and stroma, the estrogen-initiated disruption in this pattern would lead to permanent differentiation defects of the prostate gland. It is hypothesized that these molecular and cellular changes initiated early in life predispose the prostate to the neoplastic state upon aging.

Animals↗

PubMed2001

Neonatal low- and high-dose exposure to estradiol benzoate in the male rat: I. Effects on the prostate gland.

Brief exposure of rats to high doses of natural estrogens early in life results in permanent alterations of the prostate gland, which include differentiation defects, altered gene expression, and dysplasia with aging. Whether low-dose treatments can cause similar effects in the developing prostate remains controversial. The current project was designed to determine the dose-response relationship of the prostate gland to estradiol exposure during the developmentally critical neonatal period in the rat. Male Sprague-Dawley (SD) rats were treated on Days 1, 3, and 5 of life by s.c. injections of a 7-log range of doses (0.015 microg/kg to 15.0 mg/kg) of beta-estradiol-3-benzoate (EB) in 25 microl of peanut oil (Arachis) as vehicle. In a separate block, neonatal Fisher 344 (F344) rats received 0.15, 15.0, or 1500.0 microg EB/kg. Rats were killed on Postnatal Day (PND) 35 or 90, and the prostates were microdissected, weighed, and frozen for immunohistochemistry. Preputial separation and hepatic testosterone hydroxlase activities were monitored and measured to determine the onset of puberty. On PND 35, there was an increase in prostate weights of SD rats treated with low doses of EB and a decrease in prostate weights of SD rats treated with high doses. The low-dose effect was entirely abolished by PND 90, and only high-dose suppression of organ sizes was found. The transient nature of the effect in low-dose animals suggests an advancement of puberty as the cause for increased reproductive organ weights on PND 35. F344 rats were more sensitive than SD rats to the suppressive effects of high doses of neonatal EB on PND 90. Despite this heightened responsiveness in the F344 rats, a low-dose estrogenic effect on adult prostate weights was not observed. Thus, in the rat model a sustained effect at low doses of natural estrogens is not present in the prostate glands.

Aging↗

PubMed2001

Neonatal low- and high-dose exposure to estradiol benzoate in the male rat: II. Effects on male puberty and the reproductive tract.

Environmental contaminants with estrogenic properties have been cause for heightened concern about their possible role in inducing adverse health effects. Brief exposure of rodents to high doses of natural estrogens early in life results in permanent alterations of the male reproductive tissues, but the question of whether environmentally relevant doses can cause the same effects remains controversial. The current project was designed to determine the dose-response relationship between neonatal estradiol exposure and the development of the male reproductive tract in the rat. Neonatal male Sprague-Dawley (SD) and Fisher 344 (F344) rats were exposed to beta-estradiol-3-benzoate (EB) at concentrations ranging from 0.015 microg/kg body weight (BW) to 15.0 mg/kg BW and 0.15 microg/kg BW to 1.5 mg/kg BW, respectively. Results showed an inverted U-shaped dose-response profile for testis and epididymis weights in 35-day-old SD rats, with increased organ sizes at the low-dose end of the treatment. This effect was transient and was not sustained into adulthood. Increased hepatic testosterone hydroxylase activities in low-dose animals suggest an advancement of puberty as the cause for increased reproductive organ weights. On postnatal day (PND) 90, a stimulatory low-dose response to EB was present in SD rat testicular and epididymal weights, however at one order of magnitude lower dose than that seen on PND 35, suggesting a separate effect. All SD male reproductive tract organs and serum hormones showed a permanent inhibitory response to high doses of neonatal EB. F344 rats exhibited greater estrogen sensitivity on PND 90. Despite this heightened responsiveness, F344 rats did not exhibit a low-dose effect for any endpoint. These low-dose responses to estradiol are organ and strain specific.

Aging↗

PubMed2001

Developmental exposure to estrogens alters epithelial cell adhesion and gap junction proteins in the adult rat prostate.

Brief exposure to estrogens during the neonatal period interrupts rat prostatic development by reducing branching morphogenesis and by blocking epithelial cells from entering a normal differentiation pathway. Upon aging, ventral prostates exhibit extensive hyperplasia and dysplasia suggesting that neonatal estrogens may predispose the prostate gland to preneoplastic lesions. To determine whether these prostatic lesions may be manifested through aberrant cell-to-cell communications, the present study examined specific gap junction proteins, Connexins (Cx) 32, and Cx 43, and the cell adhesion molecule, E-cadherin, in the developing, adult and aged rat prostate gland. Male rat pups were given 25 microgram estradiol benzoate or oil on days 1, 3, and 5 of life. Prostates were removed on days 1, 4, 5, 6, 10, 15, 30, or 90 or at 16 months, and frozen sections were immunostained for E-cadherin, Cx 43, and Cx 32. Colocalization studies were performed with immunofluorescence using specific antibodies for cell markers. Gap junctions in undifferentiated epithelial cells at days 1-10 of life were composed of Cx 43, which always colocalized with basal cell cytokeratins (CK 5/15). Cx 32 expression was first observed between days 10-15 and colocalized to differentiated luminal cells (CK 8/18). Cx 43 and Cx 32 never colocalized to the same cell indicating that gap junction intercellular communication differs between basal and luminal prostatic cells. While epithelial connexin expression was not initially altered in the developing prostates following estrogen exposure, adult prostates of neonatally estrogenized rats exhibited a marked decrease in Cx 32 staining and an increased proportion of Cx 43 expressing cells. In the developing prostate, E-cadherin was localized to lateral surfaces of undifferentiated epithelial cells and staining intensity increased as the cells differentiated into luminal cells. By day 30, estrogenized prostates had small foci of epithelial cells that did not immunostain for E-cadherins. In the adult and aged prostates of estrogenized rats, larger foci with differentiation defects and dysplasia were associated with a decrease or loss in E-cadherin staining. The present findings suggest that estrogen-induced changes in the expression of E-cadherin, Cx32 and Cx43 may result in impaired cell-cell adhesion and defective cell-cell communication and may be one of the key mechanisms through which changes toward a dysplastic state are mediated. These findings are significant in light of the data on human prostate cancers where carcinogenesis and progression are associated with loss of E-cadherin and a switch from Cx32 to Cx43 expression in the epithelium.

Aging↗

PubMed2001

Alterations in gap junction protein expression in human benign prostatic hyperplasia and prostate cancer.

PURPOSE: Gap junctions composed of connexin proteins have an essential role in intercellular communication and differentiation. Dysregulation of connexin expression is believed to have a role in carcinogenesis. The human prostate has been reported to express connexin 32 and 43. However, the expression pattern in prostate cancer is controversial, while to our knowledge connexin expression has not been reported in benign prostatic hyperplasia (BPH). To understand the potential involvement in prostate disease connexin 32 and 43 expression was evaluated in a series of normal prostate, BPH and prostate cancer specimens that were surgically removed due to bladder outlet obstruction. MATERIALS AND METHODS: Frozen sections of 23 normal, 43 BPH and 40 cancer involved prostates were evaluated for the presence, staining intensity and pattern of connexin 32 and 43 by immunocytochemical testing. RESULTS: In all specimens examined connexin 43 stain was punctate along the borders of the basal epithelial cells, whereas connexin 32 immunolocalized to luminal epithelial cells. In normal prostate connexin 43 and 32 were present in 87% and 65% of specimens, respectively, at low to moderate stain intensity. Importantly none of the normal samples were negative foreach connexin. In BPH specimens there was a marked increase in the incidence and intensity of connexin 43 and 32 immunostaining within epithelial cells. In addition, 23% of BPH samples showed strong connexin 43 expression in stromal cells. In contrast, connexin was decreased in prostate cancer specimens, of which 65% and 38% were negative for connexin 43 and 32, respectively, and 28% were negative for each type. In poorly differentiated tumors connexin 43 and 32 were present in only 10% and 40% of tumors, respectively, at low immunostaining intensity. CONCLUSIONS: In normal human prostate basal cells communicate via connexin 43 gap junctions, whereas luminal cells communicate via connexin 32 gap junctions. In BPH gap junctional intercellular communication is increased in epithelial and stromal cells, which may have a role in BPH pathogenesis. In prostate cancer gap junctional intercellular communication is decreased, is as indicated by decreased expression of connexin 43 and 32 with severe loss in poorly differentiated prostate cancer. These alterations in connexin expression may have a role in dedifferentiation and tumor progression.

Adenocarcinoma↗

PubMed2000

Distribution of mRNAs encoding CRF receptors in brain and pituitary of rat and mouse.

Two G protein-coupled receptors have been identified that bind corticotropin-releasing factor (CRF) and urocortin (UCN) with high affinity. Hybridization histochemical methods were used to shed light on controversies concerning their localization in rat brain, and to provide normative distributional data in mouse, the standard model for genetic manipulation in mammals. The distribution of CRF-R1 mRNA in mouse was found to be fundamentally similar to that in rat, with expression predominating in the cerebral cortex, sensory relay nuclei, and in the cerebellum and its major afferents. Pronounced species differences in distribution were few, although more subtle variations in the relative strength of R1 expression were seen in several forebrain regions. CRF-R2 mRNA displayed comparable expression in rat and mouse brain, distinct from, and more restricted than that of CRF-R1. Major neuronal sites of CRF-R2 expression included aspects of the olfactory bulb, lateral septal nucleus, bed nucleus of the stria terminalis, ventromedial hypothalamic nucleus, medial and posterior cortical nuclei of the amygdala, ventral hippocampus, mesencephalic raphe nuclei, and novel localizations in the nucleus of the solitary tract and area postrema. Several sites of expression in the limbic forebrain were found to overlap partially with ones of androgen receptor expression. In pituitary, rat and mouse displayed CRF-R1 mRNA signal continuously over the intermediate lobe and over a subset of cells in the anterior lobe, whereas CRF-R2 transcripts were expressed mainly in the posterior lobe. The distinctive expression pattern of CRF-R2 mRNA identifies additional putative central sites of action for CRF and/or UCN. Constitutive expression of CRF-R2 mRNA in the nucleus of the solitary tract, and stress-inducible expression of CRF-R1 transcripts in the paraventricular nucleus may provide a basis for understanding documented effects of CRF-related peptides at a loci shown previously to lack a capacity for CRF-R expression or CRF binding. Other such "mismatches" remain to be reconciled.

Animals↗

PubMed2000

Androgen receptor-immunoreactivity in the forebrain of the Eastern Fence lizard (Sceloporus undulatus).

Androgen receptor (AR) distribution in the lizard forebrain and optic tectum was examined using PG21 immunohistochemistry. In the male Eastern Fence lizard, AR-immunoreactive (-ir) nuclei were observed in the medial preoptic area, ventromedial and arcuate hypothalamic nuclei, periventricular hypothalamus, premammillary nucleus, bed nucleus of the stria terminalis, and ventral posterior amygdala. Punctate immunostaining of neuronal processes (axons and/or dendrites) was concentrated in the cortex, hypothalamus, and optic tectum. AR-ir nuclei in the female brain were confined to the ventral posterior amygdala and ventromedial hypothalamic nucleus. The AR distribution in the lizard brain is similar to that reported for other vertebrate classes. Sex differences in AR-immunoreactivity may contribute to sex-specific behaviors in the Eastern Fence lizard.

Animals↗

PubMed2000

In vitro fertilization outcomes after intracytoplasmic sperm injection with fresh or frozen-thawed testicular spermatozoa.

OBJECTIVE: To compare the outcomes of intracytoplasmic sperm injection (ICSI) and in vitro fertilization (IVF) with fresh and cryopreserved testicular spermatozoa in patients with obstructive and nonobstructive azoospermia. DESIGN: Retrospective analysis of consecutive ICSI cycles. SETTING: Large urban reproductive medicine program. PATIENT(S): Twenty-nine patients with obstructive and nonobstructive azoospermia undergoing testicular sperm extraction for a total of 46 IVF-ICSI cycles (12 fresh, 34 frozen). INTERVENTION(S): Testicular sperm extraction, cryopreservation, and IVF-ICSI with fresh or frozen-thawed spermatozoa. MAIN OUTCOME MEASURE(S): Fertilization rates, embryo cleavage rates, embryo implantation rates, clinical pregnancy rates per cycle and per embryo transfer, and delivery and spontaneous abortion rates. RESULT(S): No statistically significant differences were noted in any of the parameters examined between IVF-ICSI cycles from fresh or frozen-thawed testicular spermatozoa. Fertilization rates were 56% with fresh vs. 61% with frozen-thawed testicular sperm, cleavage rates 92% vs. 95%, implantation rates 26% vs. 17%, clinical pregnancy rates per cycle 33% vs. 41%, and pregnancy rates per embryo transfer 33% vs. 45%, respectively. Delivery rates were 75% with fresh vs. 69.2% with frozen-thawed testicular sperm, and spontaneous abortion rates 25% and 30.8%, respectively. CONCLUSION(S): No differences were found in IVF-ICSI outcomes between cryopreserved and fresh testicular sperm. In addition, cryopreservation provides several advantages for the patients and reproductive team.

Adult↗

PubMed2000

Evidence that estrogens directly alter androgen-regulated prostate development.

Neonatal exposure to high doses of estrogen results in permanent suppression of prostate growth and reduced sensitivity to androgens in adulthood. It is unclear whether alterations in prostate growth are due to a direct effect of estrogens on the gland or are the result of hypothalamic-pituitary-gonadal axis suppression and a subsequent reduction in androgen levels. Therefore, the aim of this study was to determine whether estrogens have a direct effect on the prostate using a defined method of culturing neonatal prostates. Newborn rat ventral prostates were microdissected and cultured in the presence of testosterone, which resulted in branching morphogenesis and ductal canalization. Solid cords of epithelium differentiated into acini lined by tall columnar epithelial cells; these acini were surrounded by stromal cells, expressing smooth muscle alpha-actin. When cultured in the presence of 17beta-estradiol or diethylstilbestrol in addition to testosterone, androgen-induced prostatic growth was reduced, and differentiation was altered. Although estrogen-treated explants were smaller than controls, quantification of epithelial, stromal, and luminal volumes using unbiased stereology revealed significant changes; the proportion of epithelial cells and lumen decreased, and the proportion of stroma increased compared with control values. Concurrent with this reduced growth rate, we observed a disturbance in the branching pattern and a reduction in ductal canalization. Specifically, stromal differentiation and organization were disrupted, so that a discontinuous smooth muscle layer was observed around the epithelial ducts, and epithelial differentiation was altered. The effects of estrogens were not accompanied by a decrease in androgen response via the androgen receptor, because immunolocalization of this receptor remained constant. These data demonstrate that high doses of estrogens are growth inhibitory and have direct effects on prostate development in vitro, which may occur in vivo in addition to indirect effects via suppression of the hypothalamic-pituitary-gonadal axis.

Actins↗

PubMed2000

Molecular biology of the androgen receptor.

The androgen receptor is a member of a superfamily of nuclear transcription factors that mediate the action of steroid hormones. When activated by ligand binding, these transcription factors bind to specific DNA sequences on target genes and regulate the transcriptional activity of those genes. Various genes have been identified that are regulated by androgens, including prostate-specific antigen (PSA). PSA contains an upstream glucocorticoid response element/androgen response element, so it is believed that androgens directly regulate its transcription rate. Despite this, posttranscriptional regulation through stability of the messenger RNA product is believed to be a major mechanism of androgens' effects.

Androgens↗

PubMed1999

Estrogen receptor-beta: implications for the prostate gland.

Estrogens can have profound effects on prostate growth and differentiation. These effects were thought to be mediated by the classical estrogen receptor; however, the discovery of a second estrogen receptor has redefined the estrogen signaling pathway and may have broad implications on estrogen-responsive tissues, including the prostate. The new estrogen receptor, named estrogen receptor-beta (ERbeta), is preferentially expressed in the prostate and maintains some characteristics that are different from ERalpha. Establishing the distribution and function of ERbeta in the various estrogen-responsive tissues is critical to defining its pharmacological and physiological impact. Differential expression of ERbeta may facilitate development of tissue-specific estrogen agonists and antagonists, a goal in the treatment of diseases in estrogen-sensitive tissues such as breast cancer. This article reviews the current knowledge on ERbeta and its potential impact on the prostate.

Animals↗

PubMed1999

Androgen receptors and sexual dimorphisms in the larynx of the bullfrog.

As in most anuran amphibians, both male and female bullfrogs (Rana catesbeiana) vocalize. Sex differences in vocalizations in the bullfrog may be due to sex differences in the larynx. We examined the laryngeal muscle to determine whether it possessed androgen receptors and whether there were morphological sexual dimorphisms in the larynx. Using a polyclonal antibody and immunocytochemistry, we found androgen receptors in the laryngeal dilator muscle of both sexes. Males possessed approximately 13% more receptor-positive muscle nuclei than females. We also stained the dilator muscle for the presence of succinate dehydrogenase. Density of staining for the enzyme was significantly greater in male muscle than in female muscle, indicating greater oxidative capacity of muscle in males. This procedure also showed both a significantly greater cross-sectional area for the dilator muscle in males and a greater area for individual fibers. Male muscle consisted almost entirely of fast-twitch oxidative/glycolytic fibers. Female muscle contained a mixture of fast-twitch glycolytic fibers and two subclasses of fast-twitch oxidative/glycolytic fibers. Finally, both the length and width of the entire laryngeal complex and the length and width of the dilator were significantly greater in males than in females. In summary, laryngeal muscle of bullfrogs possessed androgen receptors and is thus likely to be androgen sensitive. Androgens, during development or at adulthood, may be responsible for the anatomic and enzymatic sexual dimorphisms in the larynx.

Animals↗