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At least 577 records · Page 32Linked to original sources
PubMed1989

Autoradiographic studies of androgen-binding sites in human benign prostatic hyperplasia in vitro.

Steroid autoradiographic techniques were used to visualize the distribution of androgen receptor-positive cells in human benign prostatic hyperplasia grown in organ culture. The tissue consisted of alveoli embedded in dense fibromuscular stroma and lined either with one row of cuboidal secretory cells or with several layers of epithelial cells. In some explants alveoli were seen lined with spindle-shaped cells. The autoradiographs showed that in most explants both epithelium and stroma contained androgen receptor-positive cells but that the uptake was less pronounced in the stromal cells. In alveoli lined with several cell layers the basal cells seemed to incorporate less androgen than secretory cells on the luminal side. In alveoli lined with spindle-shaped cells, these were always androgen receptor-negative.

Aged↗
PubMed1994

Androgen and oestrogen responsiveness of stromal cells derived from the human hyperplastic prostate: oestrogen regulation of the androgen receptor.

Stromal cells derived from collagenase-digested benign hyperplastic adult prostates were isolated and grown in culture. Androgen and oestrogen receptor status were determined and growth in response to mibolerone (a synthetic androgen) and oestradiol-17 beta was measured. In addition, the ability of oestrogens to regulate the androgen receptor in stromal cells was investigated. [3H]Thymidine incorporation into DNA was stimulated by mibolerone in primary and secondary cultures, but sensitivity was lost with subsequent passages. Androgen stimulation of [3H]thymidine incorporation was consistently inhibited by the anti-androgen cyproterone acetate. Oestradiol-17 beta also stimulated [3H]thymidine incorporation into DNA, and this effect was inhibited by the anti-oestrogen tamoxifen. Sensitivity to oestradiol was lost with subsequent passages. A combination of mibolerone and oestradiol was not synergistic in increasing [3H]thymidine incorporation into DNA, but maximal stimulation occurred at 100-fold lower concentrations of mibolerone and oestradiol when the two hormones were applied in combination. Specific high-affinity [3H]mibolerone- and [3H]oestradiol-binding sites were demonstrated by radioligand binding in intact cells. The affinity for oestradiol binding to its receptor exceeded that quantified for mibolerone binding to the androgen receptor, whilst the number of oestradiol-binding sites was approximately tenfold less than that quantified for mibolerone. Treatment with oestradiol down-regulated the number of [3H]mibolerone binding sites 1.7-fold (P < 0.005) as early as day 2 after oestradiol treatment. In conclusion, we successfully cultured stromal cells derived from hyperplastic prostates which retained sensitivity to androgen and oestrogen.(ABSTRACT TRUNCATED AT 250 WORDS)

Cells, Cultured↗
PubMed1996

Benign prostatic stromal cells are regulated by basic fibroblast growth factor and transforming growth factor-beta 1.

The current study was undertaken, using cultures of prostatic epithelial and stromal cells, to determine the functional interactions between androgens, basic fibroblast growth factor (FGF2) and transforming growth factor-beta 1 (TGF beta 1) and their importance in maintaining stromal homeostasis. Treatment of stromal cells with TGF beta 1 significantly increased intracellular FGF2 and FGF2 sequestered to the extracellular matrix. FGF2 was also detected in stromal conditioned medium (SCM), but at levels 70-fold less than found in cell lysates. TGF beta 1 (0.1 ng/ml) treatment caused an initial increase of 86% in secreted FGF2 levels, but high concentrations of TGF beta 1 (5 ng/ml) decreased FGF2 levels by 38%, relative to the untreated control. Further studies showed that epithelial conditioned medium (ECM), androgen-treated, stromal conditioned medium (ASCM), but not SCM were mitogenic for stromal cells. Both ECM and ASCM caused a threefold increase in DNA synthesis. FGF2 may be the mediator of these interactions, since the mitogenic effect of both ECM and ASCM was significantly reduced by the addition of anti-FGF2 neutralising antibody. We hypothesise that the lack of response of stromal cells to SCM is due to TGF beta 1 blocking the mitogenic effect of FGF2. Thus down-regulation of TGF beta 1 synthesis, by androgens, results in stromal proliferation by ASCM.

Cell Division↗
PubMed1998

Balding hair follicle dermal papilla cells contain higher levels of androgen receptors than those from non-balding scalp.

Androgens can gradually transform large scalp hair follicles to smaller vellus ones, causing balding. The mechanisms involved are unclear, although androgens are believed to act on the epithelial hair follicle via the mesenchyme-derived dermal papilla. This study investigates whether the levels and type of androgen receptors in primary lines of cultured dermal papilla cells derived from balding scalp hair follicles differ from those of follicles from non-balding scalp. Androgen receptor content was measured by saturation analysis using the non-metabolisable androgen, [3H]mibolerone (0.05-10 nM) in a 9-10 point assay. Pubic dermal fibroblasts and Shionogi cells were examined as positive controls. Repetitive assays of Shionogi cells showed good precision in the levels of androgen receptor content (coefficient of variation = 3.7%). Specific, high affinity, low capacity androgen receptors were detected in dermal papilla cells from both balding and non-balding follicles. Balding cells contained significantly (P < 0.01) greater levels of androgen receptors (Bmax = 0.06 +/- 0.01 fmol/10(4) cells (mean +/- S.E.M.)) than those from non-balding scalp (0.04 +/- 0.001). Competition studies with a range of steroids showed no differences in receptor binding specificity in the two cell types. The higher levels of androgen receptors in cells from balding scalp hair follicles with similar properties to those from non-balding scalp concur with the expectations from their in vivo responses to androgens. This supports the hypothesis that androgens act via the dermal papilla and suggests that cultured dermal papilla cells may offer a model system for studying androgen action in androgenetic alopecia.

Adult↗
PubMed2005

Androgen receptor pathway in rats with autosomal dominant polycystic kidney disease.

Androgens have been implicated in mediating disease escalation in autosomal dominant polycystic kidney disease (ADPKD). Dihydrotestosterone (DHT), an agonist, and flutamide (FLT), an antagonist, were administered to Han:SPRD rats with ADPKD, and the role of androgen receptor (AR) abundance and activation on the enlargement and function of cystic kidneys was evaluated. Renal AR abundance determined by immunoblots in 8- to 10-wk-old Cy/+ male rats was naturally increased four-fold above that of littermate +/+ controls. In male Cy/+, castration decreased AR abundance below control +/+ by -89.4%, and AR expression within cyst mural epithelial cells was strikingly decreased. Castration of Cy/+ male rats also reduced the usual increases in kidney weight by -49.7%, kidney cyst area by -34.0%, and serum urea nitrogen by -72.8%; these indices were restored to precastration levels by DHT. In Cy/+ male rats, FLT administration reduced the increase in kidney weight by -27.6% and serum urea nitrogen by -53.7% and decreased the increment in AR expression by -84.2% in comparison with untreated +/+ controls. There was no effect of FLT in female rats. Immunoblot expression of phospho-extracellular signal-regulated kinase 1/2 (P-ERK) and B-Raf, key intermediates in the mitogen-activated protein kinase pathway that are abnormally elevated in Cy/+, was unaffected by castration and/or administration of DHT or FLT. AR was not expressed in renal epithelial cell nuclei of androgen-deficient rats but was displayed in most tubule and mural cyst cell nuclei of androgen-replete rats. In androgen-deficient Cy/+, 80.6% of renal epithelial cells that had entered the cell cycle (proliferating cell nuclear antigen positive) also expressed P-ERK. In androgen-replete rats, proliferating cell nuclear antigen-positive cells co-expressed AR (12.7%), P-ERK (36.4%), and P-ERK + AR (45.0%); 5.9% were probably stimulated by other mitogenic mechanisms. It is concluded that androgens potentiate renal cell proliferation and cyst enlargement through ERK1/2-dependent and ERK1/2-independent signaling mechanisms in Han:SPRD. It is suggested that the basal rate of cell proliferation is determined by ERK1/2 signaling to a major extent and that androgens have additive effects.

Androgen Antagonists↗
PubMed2001

Effects of three vertebrate hormones on the growth, development, and reproduction of the tomato moth, Lacanobia oleracea L. (Lepidoptera: Noctuidae).

In recent years, concern has been growing that numerous manmade chemicals entering the environment are capable of mimicking endogenous hormones in wildlife. In an attempt to define and evaluate the possible impact of endocrine-disrupting substances (EDS) on insects, three vertebrate hormones were tested for their effects on growth, development, and reproduction of the tomato moth. Lacanobia oleracea. Dietary administration of estrogen or thyroxine caused a significant increase in the length of the third, fourth, fifth, and sixth larval stadia (p < 0.001). The mean time for development of the pupa, however, was not significantly different between treatments. Relative to the control groups, a significant (p < 0.05) reduction in the mean weights of fifth- and sixth-instar larvae was also observed when larvae were exposed to estrogen or thyroxine and in pupae derived from insects exposed to thyroxine or testosterone (p < 0.001). Despite this, the number of larvae that survived to adulthood was not affected by any of the treatments; neither was the pupal sex ratio affected. However, exposure of larvae to testosterone significantly (p < 0.05) increased the number of deformed pupae. In addition, the reproductive potential of adults derived from the testosterone treatment was markedly reduced. Exposure of L. oleracea larvae to this steroid caused a highly significant (p < 0.001) decrease in egg production. coupled with a significant (p < 0.05) decrease in egg viability. The physiological effects observed in L. oleracea and their possible causes are presented in this paper, and the likely impact of EDS and their effects on terrestrial invertebrates are discussed.

Administration, Oral↗
PubMed2000

Growth-promoting systems for heifer calves and yearlings finished in the feedlot.

In a 172-d finishing trial (Exp. 1), 210 recently weaned crossbred heifers were allotted to six growth promotant treatment groups, involving implanting initially with Synovex-C (C) or H (H) followed by reimplanting with Finaplix-H (F) or H and F. Melengestrol acetate (MGA) was provided in the diet to four of the treatment groups. Heifers fed MGA and administered only F as the terminal implant had the greatest (P = .01) number of mature ovaries with follicles but also had lower (P = .01) gain/DMI. In a 182-d finishing study (Exp. 2), 270 recently weaned crossbred heifers were allotted to the following six implant (d 0)/ reimplant (d 70) groups using no implant (N), Ralgro (R) or H: N/R, R/H, R/R, N/R, H/H and R/R for Treatments 1 through 6, respectively. On d 70, all heifers were implanted with F. Heifers were fed MGA from d 70 to 182 (Treatments 1, 2, and 3) or for the entire trial (Treatments 4, 5, and 6). Implanting on d 0 increased (P < .05) overall ADG. Differences (P > .05) in performance were not found between MGA treatment groups. Using an H implant/reimplant regimen decreased (P = .01) ovarian and(or) follicular development when compared with an R implant/reimplant regimen. In a 126-d finishing trial (Exp. 3), 360 crossbred yearling heifers were used to evaluate F and estrogen (Implus-H) implants when used in combination with an MGA feeding program. Heifers receiving only F in combination with MGA had greater (P < .05) ADG, whereas all heifers fed MGA had greater (P < .05) gain/DMI than heifers not fed MGA. These data suggest that feeding MGA was not beneficial for young heifers, particularly if they are provided an initial estrogenic implant followed by a second implant. In older (yearling) heifers, increased gains and gain/DMI were obtained by feeding MGA and implanting initially or 56 d later with F.

Animal Feed↗
PubMed2007

Hormone treatment enhances WT1 activation of Renilla luciferase constructs in LNCaP cells.

The zinc finger transcription factor, WT1, regulates many growth control genes, repressing or activating transcription depending on the gene and cell type. Based on earlier analyses of the effect of WT1 on androgen responsive genes, we hypothesized that there may be an interaction between the androgen signaling pathway and WT1, such that the commonly used Renilla luciferase control vectors were activated in LNCaP prostate cancer cells. Using cotransfection assays we tested the effects of WT1 and/or the androgen analog, R1881, on two Renilla luciferase vectors, pRL-SV40 and the promoter-less pRL-null. To determine whether the zinc finger DNA binding domain was required, the zinc finger mutant DDS-WT1 (R394W) was tested; but it had no significant effect on the Renilla luciferase vectors. To determine whether the androgen signaling pathway was required, WT1 was co-transfected with Renilla vectors in cells with varied hormone responsiveness. The WT1 effect on pRL-null varied from no significant effect in 293 and PC3 cells to very strong enhancement in LNCaP cells treated with 5 nM R1881. Overall, these results suggest that hormone enhanced WT1 mediated activation of Renilla luciferase and that these interactions require an intact WT1 zinc finger DNA binding domain.

Cell Line, Tumor↗
PubMed2007

Regulation of vascular endothelial growth factor, VEGF, gene promoter by the tumor suppressor, WT1.

Understanding angiogenesis and growth control is central for elucidating prostate tumorigenesis. However, the mechanisms of activation of the angiogenic gene, vascular endothelial growth factor (VEGF) are complex and its regulation in prostate cancer is not well understood. In previous studies, VEGF expression levels were correlated with altered levels of the zinc finger transcription factor, WT1. Since the VEGF promoter has several potential WT1 binding sites and WT1 regulates many growth control genes, here we assessed whether WT1 might also regulate VEGF transcription. Using transfection and DNA binding assays, functional WT1 binding sites were localized within the proximal VEGF promoter. Transfection of the DDS-WT1 (R394W) zinc finger mutant had no significant effect on VEGF-luciferase reporter activity, suggesting that an intact zinc finger DNA binding domain was required. Interestingly, WT1-mediated regulation of VEGF reporter constructs varied in different cell types. In androgen-responsive, LNCaP prostate cancer cells, hormone treatment enhanced WT1-mediated activation of the VEGF promoter constructs. Overall, these results suggest that WT1 transcriptionally regulates VEGF through interaction of its zinc finger DNA binding domain with the proximal GC-rich VEGF promoter. These findings may shed light on the role of WT1 in angiogenesis and prostate cancer progression.

Binding Sites↗
PubMed1991

Clinical assessment and urine testing for anabolic-androgenic steroid abuse and dependence.

The emerging epidemic of anabolic-androgenic steroid use, no longer confined to elite athletes, is associated with adverse health consequences for which users may seek treatment. As with other forms of drug abuse, patients may deny or hide their use of steroids while seeking treatment for bothersome side effects or other problems. Thus, clinicians may increasingly, but unknowingly, see patients who are using steroids. Early detection and treatment of steroid abuse and dependence is critical in order to prevent serious and potentially fatal consequences. Therefore, it is incumbent upon clinicians to know the signs and symptoms of using steroids, and to be familiar with the clinical indications for urine testing. Using case examples, the authors review the assessment of steroid abuse and dependence in clinical practice and illustrate the role of urine testing in the assessment process.

Adult↗
PubMed1981

Temporal and quantitative correlations between nuclear androgen binding and stimulation of rna polymerase II activity in Sertoli cells.

The nuclear accumulation of 3H-androgen had been correlated with the effects of this steroid on nuclear RNA polymerase activity in the Sertoli cell under identical experimental conditions. The synthetic androgen methyltrienolone (R1881) was chosen to avoid ambiguities caused by metabolism of the radioligand. Nuclear accumulation of specifically bound 3H-R1881 was apparent after 5 min and preceded RNA polymerase II activation. RNA polymerase II activity was significantly increased by 10 min after administration of R1881, and the response was maximal at 15 min. Although nuclear binding of 3H-R1881 continued to increase over this interval, the enzyme activity declined to basal levels by 20 min. Saturation of nuclear binding sites required concentrations of R1881 that were approximately one order of magnitude higher than those required for maximal polymerase II activation at 15 min. The results indicate that occupancy of only a small fraction of the specific nuclear binding sites by androgen is required to elicit maximal elevation of RNA polymerase II activity in cultured Sertoli cells.

Animals↗
PubMed1989

Analysis of the androgen binding in human benign prostatic hypertrophy.

In order to delineate optimal conditions for the determination of androgen specific binding in human benign prostatic hypertrophy tissues (BPH), extracts of these tissues were prepared using buffers of different compositions. The binding of 5 alpha-dihydrotestosterone (DHT) and of methyltrienolone (R 1881) was analyzed using agar gel electrophoresis. This method allowed the detection of 3 different high affinity tissular binding peaks with similar specificity. Moreover, the inhibition by each of the competitors was also the same for both ligands. It could be demonstrated that none of the observed peaks resulted from the binding of 1 of the ligands to sex hormone binding globulin (SHBG) or to a progesterone receptor. Hypotheses about the possible origin of these peaks are discussed.

Binding, Competitive↗