Androgen Receptor In Epithelial Cells Research Articles

The process of testicular regression also impacts the physiology of the epididymis of the bat Molossus molossus, although with a delay in epididymal response due to sperm storage

Responsible for post-testicular maturation, concentration, protection and sperm storage, the epididymis is an organ that can be easily subdivided into three segments: caput, corpus and cauda. Each epididymal region displays different morphology and functions within the sperm maturation process. Despite the great importance of this organ, studies on its morphology and hormonal control in bats remain scarce. Thus, the aim of this study was to morphologically analyze the epididymis of the bat Molossus molossus (Chiroptera: Molossidae), in order to evaluate its morphological and morphometric variations, as well as some aspects of its hormonal control during the annual reproductive cycle. For this purpose, 60 sexually adult males were used in this study, comprising five specimens collected monthly for one year to form 12 sample groups. The epididymis was subjected to morphological, morphometric and immunohistochemical analyses. The results demonstrated that the processes of total testicular regression and posterior recrudescence suffered by M. molossus also impacts the physiology of the epididymis, however, a delay in the epididymal response is seen due to the storage of sperm. Similar to other mammals, the epididymis of M. molossus has a large predominance of principal and basal cells. The epididymal seasonal variations appear to be directly correlated to rainfall and photoperiod, but not to temperature. Meanwhile, epididymal physiology appears to be regulated, at least partially, by the expression of the androgen receptor in epithelial cells, which has agonist effects on cell proliferation.

Androgen Receptors in Epithelial Cells Regulate Thymopoiesis and Recent Thymic Emigrants in Male Mice.

Androgens have profound effects on T cell homeostasis, including regulation of thymic T lymphopoiesis (thymopoiesis) and production of recent thymic emigrants (RTEs), i. e., immature T cells that derive from the thymus and continue their maturation to mature naïve T cells in secondary lymphoid organs. Here we investigated the androgen target cell for effects on thymopoiesis and RTEs in spleen and lymph nodes. Male mice with a general androgen receptor knockout (G-ARKO), T cell-specific (T-ARKO), or epithelial cell-specific (E-ARKO) knockout were examined. G-ARKO mice showed increased thymus weight and increased numbers of thymic T cell progenitors. These effects were not T cell-intrinsic, since T-ARKO mice displayed unaltered thymus weight and thymopoiesis. In line with a role for thymic epithelial cells (TECs), E-ARKO mice showed increased thymus weight and numbers of thymic T cell progenitors. Further, E-ARKO mice had more CD4+ and CD8+ T cells in spleen and an increased frequency of RTEs among T cells in spleen and lymph nodes. Depletion of the androgen receptor in epithelial cells was also associated with a small shift in the relative number of cortical (reduced) and medullary (increased) TECs and increased CCL25 staining in the thymic medulla, similar to previous observations in castrated mice. In conclusion, we demonstrate that the thymic epithelium is a target compartment for androgen-mediated regulation of thymopoiesis and consequently the generation of RTEs.

PD33-11 CD3+ T CELLS SUPPRESS ANDROGEN RECEPTOR IN BPH VIA IL-1β/MIR-15B-5P SIGNALING TO AFFECT 5 ALPHA REDUCTASE INHIBITOR TREATMENT

You have accessJournal of UrologyBenign Prostatic Hyperplasia: Medical & Non-surgical Therapy (PD33)1 Apr 2020PD33-11 CD3+ T CELLS SUPPRESS ANDROGEN RECEPTOR IN BPH VIA IL-1β/MIR-15B-5P SIGNALING TO AFFECT 5 ALPHA REDUCTASE INHIBITOR TREATMENT Hualin Song*, shuai hu, and Jie Jin Hualin Song*Hualin Song* More articles by this author , shuai hushuai hu More articles by this author , and Jie JinJie Jin More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000904.011AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: 5 alpha reductase inhibitor (5ARI) is widely used in the treatment of benign prostatic hyperplasia (BPH), and has achieved good therapeutic effects, but 30%-40% of patients still have poor therapeutic effect, and subsequent surgery is needed. We found that patients with poor 5ARI treatment had more infiltration of CD3+ T cells than patients with good treatment. At the same time, we found that the expression of androgen receptor (AR) in the infiltrated area of CD3+ T cells in human BPH specimen epithelial cells was reduced. However, the regulatory relationship between these two events remains unclear. The aim of this study was to investigate whether CD3+ T cells can regulate AR expression and whether it can affect the therapeutic effects of 5ARI. METHODS: Paraffin-embedded tissues obtained from TURP were used for expression of CD3 and AR protein by IHC. RWPE-1, BPH-1-AR cells (transfect AR into BPH-1 cells) and PWR-1E cells were co-cultured with/without CD3+ T cells-Molt-3 and HH cells. AR expression in BPH epithelial cells after co-cultured were detected by Western blot. Cytokines in co-cultured supernatant were detected by cytokines array and qPCR. The high-throughput sequencing was used to detect miRNAs expression in RWPE-1 and BPH-1-AR cells after co-cultured. RESULTS: Patients with poor 5ARI treatment had more infiltration of CD3+ T cells than patients with good treatment. Expression of AR in epithelial cells was reduced in the area of CD3+ T cells infiltration in clinical samples. AR expression was also significantly reduced in BPH epithelial cells after co-cultured with CD3+ T cells. IL-1β was increased in co-cultured supernatant and it was secreted by CD3+T cells. Meanwhile, miRNA-15b-5p was also significantly increased in BPH epithelial cells after co-cultured. Mechanism dissection revealed that infiltrating CD3+ T cells secreted IL-1β to up-regulate miRNA-15b-5p in BPH epithelial cells to suppress AR. Targeting these newly identified signals via IL-1β neutralizing antibody or miRNA-15b-5p inhibitor both led to partially reverse the AR reduction. CONCLUSIONS: This study was concluded that infiltrating CD3+ T cells could suppress AR to in BPH via modulation of IL-1β/miR-15b-5p signaling. The AR level that has been reduced makes the effect of 5ARI no longer obvious, which is one of the reasons for patients with poor 5ARI treatment. Targeting these newly discovered signals and 5ARI combination may improve treatment outcomes to better treat patients with BPH. Source of Funding: None. © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e709-e710 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Hualin Song* More articles by this author shuai hu More articles by this author Jie Jin More articles by this author Expand All Advertisement PDF downloadLoading ...

Impact of Male Hormonal Contraception on Prostate Androgens and Androgen Action in Healthy Men: A Randomized, Controlled Trial

Male hormonal contraception (MHC) combines hypothalamic-pituitary-gonadal axis blockade with exogenous androgen delivery to maintain extragonadal androgen end-organ effects. Concern exists that MHC may adversely impact prostate health. The objective of the study was to determine the molecular impact of MHC on intraprostatic androgen concentrations and androgen action. This was a single-blind, randomized, placebo-controlled study. The study was conducted at an academic medical center. 32 healthy men aged 25-55 yr participated in the study. Interventions included placebo, daily transdermal testosterone (T) (T-gel), T-gel + depomedroxyprogesterone acetate (T+DMPA), or T-gel + dutasteride daily (T+D) for 12 wk, and prostate biopsy during treatment wk 10. Serum and prostate androgen concentrations and prostate epithelial-cell gene expression were measured. Thirty men completed the study. Serum T levels were significantly increased in T-gel and T+D groups compared with baseline (P < 0.05) but were decreased with the addition of DMPA. Intraprostatic androgens were no different from placebo with T-gel treatment. Addition of DMPA to T resulted in 40% lower intraprostatic dihydrotestosterone (DHT) concentration (P = 0.0273 vs. placebo), whereas combining dutasteride with T resulted in a 90% decrease in intraprostatic DHT (P = 0.0012), 11-fold increased intraprostatic T (P = 0.0011), and 7-fold increased intraprostatic androstenedione (P = 0.0011). Significant differences in global or androgen-regulated prostate epithelial-cell gene expression were not observed. Androgen-regulated gene expression correlated with epithelial-cell androgen receptor and prostatic DHT in placebo, T-gel, and T+DMPA arms and with T and androstenedione levels in the T+D arm. MHC regimens do not markedly alter gene expression in benign prostate epithelium, suggesting they may not alter risk of prostate disease. Longer-term studies examining the impact of MHC on prostate health are needed.

Morphological and immunohistochemical comparison of three rat prostate lobes (lateral, dorsal and ventral) in experimental hyperprolactinemia.

The prolactin plays an important role in the regulation of growth and differentiation of prostate gland besides androgens. The goal of this study was to reveal the influence of elevated prolactin concentration on epithelial cells of prostate. We compared the morphology of epithelial cells of prostate dorsal, lateral and ventral lobes and expression of androgen receptors in these cells in rats with hyperprolactinemia and in control rats. We used sexually mature male Wistar rats. The experimental rats received metoclopramide; the control group received saline in the same way. The prostate dorsal, lateral and ventral lobes were collected routinely for light and electron microscopy. The intensity of immunohistochemical reaction of androgen receptor in epithelial cells of dorsal, lateral and ventral lobes was evaluated by measure of optical density with computer image analysis. The light and electron (transmission and scanning) microscopes were used for morphological observations. In experimental rats twofold increase in prolactin and twofold decrease in testosterone found. In experimental group the expression of androgen receptor was lower in columnar epithelial cells of dorsal and ventral lobes but higher in lateral one. We observed morphological abnormalities in columnar epithelial cells of lateral and dorsal lobes. The columnar epithelial cells of ventral lobes didn't show any morphological changes in hyperprolactinemia.

Steroid hormone receptor expression in male breast cancer

Aims To investigate expression of the steroid hormone receptors estrogen receptor (ER)-α and -β, progesterone receptor (PR) and androgen receptor (AR) in male breast cancer. Methods Specimens from 16 male breast cancers were immunostained for ERα, ERβ, PR and AR. Findings Eighty-seven percent of tumours expressed ERα, 93% PR, 87% ERβ and 87% AR. Staining for ERα and PR was confined exclusively to the nuclei of epithelial cells with some heterogeneity. Nuclear immunoreactivity was also observed with AR. Again this was restricted to epithelial cells but tended to be more uniform. ERβ was seen in the nuclei of epithelial cells and also in stromal fibroblasts and lymphocytes. Analysis of serial sections revealed a similar pattern of staining with ERβ and AR in epithelial cells. Conclusions In addition to expression of the better known steroid receptors, ERα, PR and AR, we have demonstrated a high rate of expression of ERβ in male breast cancer. This is in keeping with the generally high steroid receptor expression seen in males. However, the abundance of ERβ expressed in this small series of male breast cancer is in contrast to female breast cancer where ERβ expression is often reduced.

2,3,7,8-tetrachlorodibenzo-p-dioxin inhibits luminal cell differentiation and androgen responsiveness of the ventral prostate without inhibiting prostatic 5alpha-dihydrotestosterone formation or testicular androgen production in rat offspring.

In utero and lactational exposure to a single maternal dose of 1 microg 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)/kg causes some overt toxicity and impairs prostate growth in male offspring. As similar effects on the ventral prostate can be caused by decreased testosterone production during perinatal development, we determined whether intratesticular testosterone content, testicular responsiveness to gonadotropin stimulation, or plasma testosterone concentrations were reduced in fetal and newborn rats. Because these endpoints were not affected, the ability of TCDD exposure to inhibit synthesis of the proximal androgen in prostate development, 5alpha-dihydrotestosterone (DHT), from the circulating precursor testosterone and 5alpha-androstane-3alpha,17ss-diol (3alpha-Diol), was studied on postnatal days (PNDs) 14, 21, and 32. The ability of the ventral prostate to form DHT from 3alpha-Diol was slightly impaired on PND 14, but this transient effect was not statistically significant, and recovery was evident by PND 21. Subsequent experiments used organ culture to study the effects of in vivo TCDD exposure on androgen metabolism, androgen responsiveness, androgen receptor expression, and luminal epithelial cell differentiation after in vitro exposure to graded androgen concentrations. In utero and lactational TCDD exposure had no effect on DHT formation in organ culture, but transiently reduced the androgen -induced expression of prostatic-binding protein subunit C3, decreased ventral prostate epithelial cell androgen receptor expression, and inhibited the formation of androgen responsive luminal epithelial cells. These results suggest that TCDD exposure impairs prostate growth and androgen responsiveness by inhibiting prostatic epithelial cell differentiation.

Effects of neonatal estrogen exposure on prostatic secretory genes and their correlation with androgen receptor expression in the separate prostate lobes of the adult rat.

Brief administration of estrogen to newborn rats permanently restricts prostatic growth and testosterone sensitivity in adulthood. Previous work demonstrated that neonatal exposure to estradiol benzoate produced lobe-specific imprints in prostatic androgen receptor (AR) expression. Epithelial cell AR was markedly reduced or absent in the adult ventral and dorsal lobes, which correlated with a lack of epithelial differentiation and responsiveness. While the lateral lobe also showed reduced growth and testosterone responsiveness after neonatal estradiol benzoate, normal cell differentiation and AR levels were observed within the adult epithelium. To determine the impact that these receptor imprints have on the functional capacity of adult tissue, we herein examined the expression of lobe-specific, androgen-dependent, or androgen-responsive secretory genes in prostates of rats given neonatal estradiol benzoate and directly compared this with epithelial cell AR using histological techniques. Sprague-Dawley rat pups were given 25 micrograms estradiol benzoate or oil on days 1, 3, and 5 and killed on day 90. Prostatic mRNA was analyzed using Northern blots and in situ hybridization. Ventral lobe mRNA was hybridized with a prostate binding protein (PBP) cDNA probe, while lateral and dorsal mRNA were hybridized with RWB (seminal vesicle secretory protein or SVS-II), probasin, and DP1 cDNA probes. Sections adjacent to those used for in situ hybridization were stained for AR by immunocytochemistry. Neonatal estradiol benzoate significantly reduced ventral lobe PBP message on Northern blots, and this was not restored with adult testosterone administration. There was a direct correlation between epithelial cell AR and PBP expression, in that PBP message and protein were only present in epithelial AR-positive cells and were absent in all AR-negative epithelium. In the lateral prostate, probasin expression was unaffected by neonatal estradiol benzoate, whereas RWB was slightly reduced using Northern analysis. By in situ hybridization, these messages were observed at normal levels in lateral lobe epithelial cells of estrogenized rats, which directly correlated with the presence of AR in those cells. In the dorsal prostate, different response patterns to neonatal estradiol benzoate were found for the three secretory genes analyzed. On Northern blots, DP1 message significantly declined, probasin mRNA was modestly suppressed, and RWB expression was significantly elevated compared to those in control tissue. In situ hybridization revealed that RWB expression in estrogenized dorsal lobes was amplified in AR-positive epithelial cells, whereas AR-negative cells appeared unaltered. In summary, prostatic functional activity after neonatal estradiol benzoate exposure is affected in a lobe-specific manner, which correlates with the AR imprints in the separate lobes.