Involvement Of Androgen Receptor Research Articles

Androgen Receptor Signaling Reduces Radiosensitivity in Bladder Cancer.

Although radiotherapy often with chemotherapy has been shown to offer a survival benefit comparable with that of radical cystectomy in select patients with bladder cancer, the development of radiosensitization strategies may significantly enhance its application. Notably, emerging preclinical evidence has indicated the involvement of androgen receptor (AR) signaling in urothelial cancer progression. We here assessed whether AR signals could contribute to modulating radiosensitivity in bladder cancer cells. Ionizing radiation reduced the numbers of viable cells or colonies of AR-negative lines more significantly than those of AR-positive lines. Similarly, in AR-positive cells cultured in androgen-depleted conditions, dihydrotestosterone treatment lowered the effects of irradiation. Meanwhile, an antiandrogen hydroxyflutamide enhanced them in AR-positive cells cultured in the presence of androgens. AR knockdown or hydroxyflutamide treatment also resulted in a delay in DNA double-strand break repair 4-24 hours after irradiation. We then established "radiation-resistant" sublines and found considerable elevation of the expression of AR as well as DNA repair genes, such as ATR, CHEK1, and PARP-1, in these sublines, compared with respective controls. Furthermore, dihydrotestosterone induced the expression of these DNA repair genes in irradiated AR-positive cells, and hydroxyflutamide antagonized the androgen effects. Finally, in a mouse xenograft model, low-dose flutamide was found to enhance the inhibitory effects of irradiation, and its tumor size was similar to that of AR knockdown line with radiation alone. These findings suggest that AR activity inversely correlates with radiosensitivity in bladder cancer. Accordingly, antiandrogenic drugs may function as sensitizers of irradiation, especially in patients with AR-positive urothelial cancer. Mol Cancer Ther; 17(7); 1566-74. ©2018 AACR.

Differential Expression of miR-93 and miR-21 in Granulosa Cells and Follicular Fluid of Polycystic Ovary Syndrome Associating with Different Phenotypes

The heterogeneous and multifactorial essence of polycystic ovary syndrome (PCOS) renders a remarkable significance to microRNAs (miRNAs). Normo-androgenic (NA) and hyperandrogenic (HA) PCOS patients were compared with matched healthy women. Expression of miRNAs and TGFβ signaling genes was studied by qRT-PCR and western blotting. Effect of androgen on expression of miR-93 and miR-21 and involvement of androgen receptor were appraised. In granulosa cells (GCs), miR-93 and miR-21 showed significantly increased levels in HA patients compared to NA patients. On the contrary, follicular fluid (FF) levels of both miRNAs were significantly decreased in HA group compared to control women. No significant change in the expression of miRNAs in serum samples was detected. Furthermore, mRNA levels of SMAD7 and TGFBR2 were significantly downregulated in GCs of HA group compared to NA and control subjects. TGFBR2 protein level was significantly decreased in HA patients compared to controls. Free testosterone and free androgen index were positively correlated with expression of miR-93 and miR-21 in GCs of PCOS group. Our findings show distinct molecular signature of different subtypes of PCOS. Intermediary position of miRNAs as androgen responsive factors may play critical role in the pathogenesis of PCOS in hyperandrogenic condition.

MP88-07 ANDROGEN RECEPTOR ACTIVITY MODULATES RADIOSENSITIVITY IN BLADDER CANCER CELLS

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology IV1 Apr 2017MP88-07 ANDROGEN RECEPTOR ACTIVITY MODULATES RADIOSENSITIVITY IN BLADDER CANCER CELLS Hiroki Ide, Satoshi Inoue, Taichi Mizushima, Mototsugu Oya, and Hiroshi Miyamoto Hiroki IdeHiroki Ide More articles by this author , Satoshi InoueSatoshi Inoue More articles by this author , Taichi MizushimaTaichi Mizushima More articles by this author , Mototsugu OyaMototsugu Oya More articles by this author , and Hiroshi MiyamotoHiroshi Miyamoto More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.2732AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Although radiation therapy often with chemotherapy has been shown to offer survival rates comparable to radical cystectomy in select patients with bladder cancer, the development of radiosensitization may significantly enhance its application. Meanwhile, emerging preclinical evidence has indicated the involvement of androgen receptor (AR) signaling in urothelial cancer progression. In prostate cancer, AR has also been linked to radioresistance involving DNA repair pathways. We therefore assessed whether AR signals contribute to the sensitivity to radiotherapy in bladder cancer cells. METHODS We compared the inhibitory effects of irradiation (2 Gy) on bladder cancer cell viability or colony formation between AR-positive [e.g. UMUC3 expressing control-short hairpin RNA (shRNA), 5637 or 647V stably expressing wild-type AR] versus AR-negative lines (e.g. UMUC3 stably expressing AR-shRNA, 5637 or 647V expressing vector only) or between AR-positive lines with versus without treatment with dihydrotestosterone (DHT) or an anti-androgen hydroxyflutamide (HF). We also compared DNA double strand breaks (DSB) via γ-H2AX foci formation in these cells after irradiation. RESULTS Ionizing radiation reduced the numbers of viable cells or colonies of AR-negative lines more significantly than those of AR-positive lines. Similarly, in AR-positive cells cultured in androgen-depleted conditions, DHT treatment lowered the effects of irradiation. In AR-positive cells cultured in the presence of androgens, HF treatment then enhanced the effects of irradiation. Furthermore, the percentage of cells containing >10 γ-H2AX foci in AR-negative lines was significantly higher than that in AR-positive lines after irradiation (4, 8, 12, and 24h). DSB repair was also delayed by HF treatment in AR-positive cells after irradiation (4, 8, 12, and 24h). CONCLUSIONS These findings suggest that AR activity correlates with the sensitivity to radiotherapy in bladder cancer cells. Accordingly, anti-androgenic drugs may function as sensitizers of irradiation, especially in patients with AR-positive urothelial cancer. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e1176 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Hiroki Ide More articles by this author Satoshi Inoue More articles by this author Taichi Mizushima More articles by this author Mototsugu Oya More articles by this author Hiroshi Miyamoto More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Androgen Receptor Involvement in Rat Amelogenesis: An Additional Way for Endocrine-Disrupting Chemicals to Affect Enamel Synthesis.

Endocrine-disrupting chemicals (EDCs) that interfere with the steroid axis can affect amelogenesis, leading to enamel hypomineralization similar to that of molar incisor hypomineralization, a recently described enamel disease. We investigated the sex steroid receptors that may mediate the effects of EDCs during rat amelogenesis. The expression of androgen receptor (AR), estrogen receptor (ER)-α, and progesterone receptor was dependent on the stage of ameloblast differentiation, whereas ERβ remained undetectable. AR was the only receptor selectively expressed in ameloblasts involved in final enamel mineralization. AR nuclear translocation and induction of androgen-responsive element-containing promoter activity upon T treatment, demonstrated ameloblast responsiveness to androgens. T regulated the expression of genes involved in enamel mineralization such as KLK4, amelotin, SLC26A4, and SLC5A8 but not the expression of genes encoding matrix proteins, which determine enamel thickness. Vinclozolin and to a lesser extent bisphenol A, two antiandrogenic EDCs that cause enamel defects, counteracted the actions of T. In conclusion, we show, for the first time, the following: 1) ameloblasts express AR; 2) the androgen signaling pathway is involved in the enamel mineralization process; and 3) EDCs with antiandrogenic effects inhibit AR activity and preferentially affect amelogenesis in male rats. Their action, through the AR pathway, may specifically and irreversibly affect enamel, potentially leading to the use of dental defects as a biomarker of exposure to environmental pollutants. These results are consistent with the steroid hormones affecting ameloblasts, raising the issue of the hormonal influence on amelogenesis and possible sexual dimorphism in enamel quality.

Involvement of androgen receptor in sex determination in an amphibian species.

In mice and humans, the androgen receptor (AR) gene, located on the X chromosome, is not known to be involved in sex determination. In the Japanese frog Rana rugosa the AR is located on the sex chromosomes (X, Y, Z and W). Phylogenetic analysis shows that the AR on the X chromosome (X-AR) of the Korean R. rugosa is basal and segregates into two clusters: one containing W-AR of Japanese R. rugosa, the other containing Y-AR. AR expression is twice as high in ZZ (male) compared to ZW (female) embryos in which the W-AR is barely expressed. Higher AR-expression may be associated with male sex determination in this species. To examine whether the Z-AR is involved in sex determination in R. rugosa, we produced transgenic (Tg) frogs carrying an exogenous Z-AR. Analysis of ZW Tg frogs revealed development of masculinized gonads or ‘ovotestes’. Expression of CYP17 and Dmrt1, genes known to be activated during normal male gonadal development, were up-regulated in the ZW ovotestis. Testosterone, supplied to the rearing water, completed the female-to-male sex-reversal in the AR-Tg ZW frogs. Here we report that Z-AR is involved in male sex-determination in an amphibian species.

Involvement of androgen receptor and glucose-regulated protein 78 kDa in human hepatocarcinogenesis

Previous studies demonstrated that androgen receptor (AR) is expressed in human hepatocellular carcinoma (HCC), one of the male-dominant diseases. Glucose-regulated protein 78kDa (GRP78/Bip), which has a role in cancer development, is one of the androgen response genes in prostate cell lines. The aim of this study was to investigate the impact of AR on endoplasmic reticulum (ER)-stress signaling in human hepatoma. AR and GRP78 expressions were examined in human liver tissue panels. Human hepatoma cells stably expressing short hairpin RNA targeting AR and cells over-expressing AR were generated. The expressions of ER-stress molecules and AR were measured by real-time RT-PCR and Western blotting. The effect of AR on ER-stress responsive gene expression was examined by reporter assay. Strong positive correlation between AR mRNA and GRP78 mRNA was observed in stage I/II-HCCs. AR enhanced ER-stress responsive element activities and GRP78 expression, and regulated ER-stress response in hepatocytes. Sorafenib strongly induced significant apoptosis in HepG2 cells by the inhibition of AR and inhibition of the downstream GRP78. AR seems a co-regulator of GRP78 especially in earlier-stage HCC. AR plays a critical role in controlling ER-stress, providing new therapeutic options against HCC.

Regucalcin, a calcium-binding protein, is a new target gene in human prostate cancer?

Regucalcin was identified as a calcium (Ca2+)-binding protein playing an important role in maintenance of intracellular Ca2+ homeostasis. More recently, proteomic studies have identified it as a down-regulated gene in mouse and human hepatocellular carcinomas. In addition, regucalcin effects in kidney and liver cells, suppressing cell proliferation, inhibiting expression of oncogenes, and increasing the expression of tumor suppressor genes, have been described. Prostate cancer depends on the trophic effects of androgens, and altered Ca2+ homeostasis and signaling have been associated with the development of this pathology. Therefore, in the present study we analyzed regucalcin expression, in neoplasic and non-neoplasic prostate tissue and cells, by means of RT-PCR, western blot and immunohistochemistry. Regucalcin localizes in cell nuclei and cytoplasm and its expression was diminished in prostate cancer cases. Moreover, regucalcin immunoreactivity was negatively associated with cellular differentiation of prostate adenocarcinoma. The effect of the non-aromatizable androgen 5-alpha-dihydrotestosterone (DHT) on regucalcin expression in vitro, in LNCaP prostate cancer cells, and in vivo, in a rat animal model, was determined. Real-time PCR analysis showed that DHT downregulates regucalcin expression, an effect inhibited in the presence of both flutamide and cyclohexamide, suggesting the involvement of androgen receptor and de novo protein synthesis. The loss of regucalcin expression in prostate cancer cases and the regulation of its expression by androgens suggest that it may be associated with tumor development and/or progression.

Involvement of androgen receptor in nitric oxide production induced by icariin in human umbilical vein endothelial cells

Icariin, a flavonoid isolated from Epimedii herba, stimulated phosphorylation of endothelial nitric oxide synthase (eNOS) at Ser1177, Akt (Ser473) and ERK1/2 (Thr202/Tyr204). The icariin-induced eNOS phosphorylation was abolished by an androgen receptor (AR) antagonist, nilutamide in human umbilical vein endothelial cells (HUVECs). Furthermore, it was also reduced in the cells transfected with small interfering RNA in which the expression of AR was broken down. The icariin-induced eNOS phosphorylation was inhibited by wortmannin, a phosphatidylinositol 3-kinase (PI3K) inhibitor and partially attenuated by PD98059, an upstream inhibitor for ERK1/2. These data suggest that icariin stimulates release of NO by AR-dependent activation of eNOS in HUVECs. PI3K/Akt and MAPK-ERK kinase (MEK)/ERK1/2 pathways were involved in the phosphorylation of eNOS by icariin.

CAG repeats in the androgen receptor gene are shorter in patients with pulmonary, esophageal or bladder carcinoma and longer in women with uterine leiomyoma.

Preferential occurrence of pulmonary, esophageal and bladder carcinomas in males indicate a possible involvement of androgen receptor (AR)-mediated functions. We evaluated the roles of the CAG repeat polymorphism in AR exon 1 in development of these lesions. The exon 1 of AR gene was amplified in samples from 198 male patients with lung carcinoma, 183 with esophageal carcinoma, 95 with bladder carcinoma and 94 males with appendicitis, as a reference group. Mean numbers of the CAG repeat in these 3 cancer groups were determined to be 20.2, 20.0 and 20.0, respectively, all being significantly smaller than that of the reference group (21.1; P<0.05). Samples from 118 female patients with lung carcinoma and 154 females with appendicitis, as a reference group, were examined, with the mean CAG repeat number significantly smaller (19.8) than that of the female reference group (20.7; P<0.01). Samples from 108 patients with uterine leiomyoma were also examined, and their CAG repeat numbers were found to be markedly expanded (23.4; P<0.01). The patients with multiple leiomyomas tend to carry a longer CAG repeat structure, with the mean CAG repeat number longer in the multicentric multiple cases (24.1) compared to that of the unicentric, multinodular cases (22.2) and those with solitary lesions (23.1; P<0.01). These results indicate that a shorter CAG repeat structure may predispose individuals to a higher risk to some male-predominant neoplasms including pulmonary, esophageal and bladder carcinomas and a longer one confers women greater susceptibility to leiomyoma development in the uterus.

Signaling pathway of nitric oxide production induced by ginsenoside Rb1 in human aortic endothelial cells: A possible involvement of androgen receptor

Ginsenosides have been shown to stimulate nitric oxide (NO) production in aortic endothelial cells. However, the signaling pathways involved have not been well studied in human aortic endothelial cells. The present study was designed to examine whether purified ginsenoside Rb1, a major active component of ginseng could actually induce NO production and to clarify the signaling pathway in human aortic endothelial cells. NO production was rapidly increased by Rb1. The rapid increase in NO production was abrogated by treatment with nitric oxide synthetase inhibitor, L-NAME. Rb1 stimulated rapid phosphorylation of Akt (Ser473), ERK1/2 (Thr202/Thr204) and eNOS (Ser1177). Rapid phosphorylation of eNOS (Ser1177) was prevented by SH-5, an Akt inhibitor or wortmannin, PI3-kinase inhibitor and partially attenuated by PD98059, an upstream inhibitor for ERK1/2. Interestingly, NO production and eNOS phosphorylation at Ser1177 by Rb1 were abolished by androgen receptor antagonist, nilutamide. The results suggest that PI3kinase/Akt and MEK/ERK pathways and androgen receptor are involved in the regulation of acute eNOS activation by Rb1 in human aortic endothelial cells.

22. Androgen receptor involvement in the freezing response of prostate cancer cell lines

22. Androgen receptor involvement in the freezing response of prostate cancer cell lines

Androgen receptor involvement in the progression of prostate cancer.

Since the growth of prostate cancer is androgen-sensitive, metastatic disease has been treated by hormonal therapy. Almost all prostate cancer patients initially respond to hormonal therapy, but the majority gradually develop resistance. The mechanism of the change in tumors from being androgen-responsive to androgen-unresponsive is generally explained by clonal selection, adaptation, an alternative pathway of signal transduction and androgen receptor (AR) involvement. Since androgen action is mediated by ARs, abnormalities in ARs are believed to play an important role in the progression of prostate cancer. Hyperactivated AR gene mutations have been detected in 20-30% of hormone-refractory tumors and functional analyses have demonstrated a wide responsiveness to estrogens, progesterone and anti-androgens as well as to androgens. The AR is highly amplified in 30% of patients with hormone-refractory prostate cancer that has been treated by castration without anti-androgens. Immunohistochemical studies of ARs in hormone-refractory prostate cancer specimens have shown that AR protein is down-regulated. DNA hypermethylation of the AR promoter region leading to AR down-regulation has been identified in 30% of hormone-refractory prostate cancers. The AR N-terminal domain in the LNCaP cell line model is activated by interleukin-6 via mitogen-activated protein kinase and single transducers and activators of transcription 3. Epidemiological observations have shown that short CAG repeats are more frequently associated with higher transactivational function in the African-American population, which may explain racial differences in the incidence of prostate cancer. Among Japanese, a short CAG repeat appears to predict a response to hormonal therapy, indicating a positive prognostic value and good prognosis at the metastatic stage of prostate cancer. Several co-factors between ARs and the transcriptional complex have been cloned and reports indicate that steroid receptor co-activator 1 is correlated with the hormone-refractory progression of prostate cancer. Thus, ARs plays an important role in the progression of prostate cancer. Based on the findings described above, genetic diagnosis and/or molecular-targeted therapy via AR pathways can be developed for hormone-refractory states.

Abolition of hypertension-induced end-organ damage by androgen receptor blockade in transgenic rats harboring the mouse ren-2 gene.

A sexual dimorphism in hypertension has been observed in both human and laboratory animal studies. The mechanisms by which male sex hormones regulate cardiovascular homeostasis are still not yet fully understood and represent the subject of this study. The possible involvement of androgen receptors in the development of hypertension and end-organ damage in transgenic rats harboring the mouse Ren-2 renin gene [TGR(mREN2)27] was studied. Male TGR(mREN2)27 rats were treated with the androgen receptor antagonist Flutamide starting at 4 wk of age. Also, an androgen receptor mutation (testicular feminization mutation [tfm]) was introduced in these rats by crossbreeding male TGR(mREN2)27 rats with tfm rats. The resulting offspring male rats that contain the tfm mutation are insensitive to androgens. Flutamide treatment or tfm mutation produced a significant attenuation of the development of hypertension. Besides a reduction in cardiac hypertrophy, urinary albumin excretion was blunted and no histologic characteristics of end-organ damage were observed in the kidney after Flutamide treatment. Testosterone levels increased 15-fold after Flutamide treatment and 2.7-fold by the tfm mutation. Also, plasma estrogens and luteinizing and follicle-stimulating hormones were significantly increased. Plasma renin concentrations and activity but not plasma angiotensinogen were reduced. Our results indicate that androgens contribute not only to the development of hypertension, but even more importantly to end-organ damage in TGR(mREN2)27 rats.

Involvement of Androgen Receptor in 17β-Estradiol-Induced Cell Proliferation in Rat Uterus1

Although it is known that, in the uterus, estrogen receptor alpha (ERalpha) is involved in proliferation and progesterone receptor in differentiation, the role of the two other gonadal-hormone receptors expressed in the uterus, androgen receptor (AR) and estrogen receptor beta (ERbeta), remains undefined. In this study, the involvement of AR in 17beta-estradiol (E(2))-induced cellular proliferation in the immature rat uterus was investigated. AR levels were low in the untreated immature uterus, but 24 h after treatment of rats with E(2), there was an increase in the levels of AR and of two androgen-regulated genes, IGF-I and Crisp (cysteine-rich secretory protein). As expected, E(2) induced proliferation of luminal epithelial cells. These actions of E(2) were all blocked by both the antiestrogen tamoxifen and the antiandrogen flutamide. The E(2)-induced AR was found by immunohistochemistry to be localized exclusively in the stroma, mainly in the myometrium, where it colocalized with ERalpha but not with ERbeta. ERbeta, detected with two different ERbeta-specific antibodies, was expressed in both stromal and epithelial cells either alone or together with ERalpha. Treatment with E(2) caused down-regulation of ERalpha and ERbeta in the epithelium. The data suggest that, in E(2)-induced epithelial cell proliferation, ERalpha induces stromal AR and AR amplifies the ERalpha signal by induction of IGF-I. Because AR is never expressed in cells with ERbeta, it is unlikely that ERbeta signaling is involved in this pathway. These results indicate an important role for AR in proliferation of the uterus, where estrogen and androgen do not represent separate pathways but are sequential steps in one pathway.

Expression of Apocrine Differentiation Markers in Neuroendocrine Breast Carcinomas of Aged Women

Neuroendocrine (NE) breast carcinomas are a rare entity in young women; however, their frequency increases in aged patients. The present work demonstrates that NE breast carcinomas in elderly women can also express an apocrine immunophenotype and analyzes the histological and clinical aspects of such differentiation. A selected series of 50 NE tumors (positive for NE markers in ≥50% of the cells) was tested for the immunocytochemical expression of gross cystic disease fluid protein-15 (GCDFP-15). The results demonstrated that about 50% of moderately (G2) and well-differentiated (G1) NE breast carcinomas (mucinous, solid papillary, and solid cohesive histotypes) coexpressed the apocrine marker. In these cases, specific mRNA for GCDFP-15 (PIP) and for chromogranin A (ChA) was demonstrated using in situ hybridization (ISH). Carcinomas of the alveolar subtype (G2) and poorly differentiated carcinomas (G3), including one case of atypical carcinoid, were pure NE carcinomas, devoid of apocrine differentiation. The steroid receptor status of these lesions was evaluated to test a possible involvement of androgen receptors in apocrine differentiation. We demonstrated that the level of AR and the mean age of patients at diagnosis were significantly higher in apocrine than in nonapocrine differentiated tumors. The histological grade and the expression of estrogen receptor (ER) significantly influenced the prognosis of these NE carcinomas, either pure or NE-apocrine differentiated. The most original result of our study is therefore the demonstration of a possible divergent apocrine differentiation of NE breast carcinomas that might be regulated by the activation of androgen receptors in elder patients. In addition, the possibility for using Chs or GCDFP-15 serum values in the follow-up of these patients, as demonstrated in two cases of the present series, can justify the immunophenotyping of the tumors.

Neuroendocrine breast carcinomas of aged women may express apocrine differentiation markers

Neuroendocrine (NE) carcinomas of the breast are a rare entity that diffusely expresses NE markers. We here demonstrate that NE breast carcinomas in elderly women can also express apocrine immuno-phenotype, and analyze the histological and clinical aspects of such differentiation. A selected series of 50 NE tumors (positive for NE markers in >50% of the cells) was tested for the immunocytochemical expression of gross cystic disease fluid protein-15 (GCDFP-15). About 50% of moderately (G2) and well-differentiated (G1) NE breast carcinomas coexpressed the apocrine marker. In these cases specific mRNA for GCDFP-15 (PIP) and for chromogranin A was demonstrated using in situ hybridization (ISH). Carcinomas of the alveolar subtype (G2) and poorly differentiated carcinomas (G3) were pure NE carcinomas, devoid of apocrine differentiation. The steroid receptor status of these lesions was evaluated to test a possible involvement of androgen receptors (AR) in apocrine differentiation. The level of AR and the mean age of patients at diagnosis were significantly higher in apocrine than in nonapocrine differentiated tumors. The histological grade and the expression of estrogen receptor significantly influenced the prognosis of these NE carcinomas, either pure or NE-apocrine differentiated. In conclusion, NE breast carcinomas may exhibit divergent apocrine differentiation that might be regulated by the activation of AR in elderly patients. In addition, the possibility to use Chs or GCDFP-15 serum values in the follow up of these patients, as demonstrated in two cases of the present series, can justify the immunophenotyping of the tumors.

Abolition of Hypertension-Induced End-Organ Damage by Anti-Androgen Treatment in Transgenic Rats Harboring the Mouse Ren-2 Gene

P171 The possible involvement of androgen receptors in the development of hypertension and end-organ damage in transgenic rats harbouring the mouse Ren-2 renin gene [TGR(mREN2)27] was studied. Male TGR(mREN2)27 rats were treated with Flutamide (specific nonsteroidal competitive antagonist of the androgen receptor, 30 mg/kg/day) starting at 4 weeks of age. Blood pressure was monitored by telemetry until the establishment of hypertension (12 weeks of age). At the age of 12 weeks, urine was collected for albumin analysis (index of kidney damage). Then the rats were sacrificed and plasma angiotensinogen, renin and testosterone concentration, as well as kidney morphology were studied. Flutamide treatment produced a significant attenuation of the development of hypertension (systolic blood pressure: treated 189.7 ± 3.5 vs. control 222 ± 8 mm Hg). Heart hypertrophy was significantly reduced by the treatment (treated 0.35 ± 0.006 vs. control 0.43 ± 0.03 g/ 100 g b.w.). Urinary albumin excretion was blunted (treated 0.6 ± 0.1 vs. control 24.2 ± 7.7 mg/24 h) and no histological characteristics of end-organ damage were observed in the kidney after treatment. Flutamide treatment reduced plasma renin concentrations (treated 27.7 ± 2.7 vs. control 71.7 ± 28.5 ng/ ml), but not plasma angiotensinogen levels (treated 1.58 ± 0.1 vs. control 1.58 ± 0.1 μg/ ml). Testosterone levels increased 20 fold. Our results indicate that treatment with androgen receptor antagonist protects against end-organ damage and attenuate the hypertension in TGR(mREN2)27 rats.

Preliminary report of impaired oestrogen receptor‐α expression in bone, but no involvement of androgen receptor, in male idiopathic osteoporosis

Preliminary report of impaired oestrogen receptor‐α expression in bone, but no involvement of androgen receptor, in male idiopathic osteoporosis

Preliminary report of impaired oestrogen receptor-alpha expression in bone, but no involvement of androgen receptor, in male idiopathic osteoporosis.

In western countries, osteoporosis affects at least 1 in 12 of all adult males and a third of osteoporotic men have idiopathic disease (MIO). Both oestrogen and testosterone are now known to be important to the male skeleton. As normal oestrogen levels have been found in younger MIO cases, it is hypothesized that, in bone, their responses to gonadal steroids may be defective, through impaired receptor expression. This study therefore compared oestrogen receptor (ER)-alpha and androgen receptor (AR) expression, by indirect immunofluorescence and semi-quantitative image analysis, in undecalcified fresh frozen bone sections from MIO patients (33-56 years), age-matched control men (n=7), and, for reference, ovarian steroid-replete (n=7) and -deficient women (n=6). In normal men, 23%+/-SEM 6% osteoblasts and 14%+/-SEM 2% osteocytes expressed ERalpha protein, similar to hormone-replete women. Although receptor expression decreased in hormone-deficient women, loss of ERalpha protein in MIO patients was more severe (1%+/-SEM 0.5% osteocytes, 2%+/-SEM 1% osteoblasts expressed receptor). In all four groups, there was little osteocyte AR expression, but in the women, a proportion of osteoblasts were receptor-positive. Deficient osteoblast and osteocyte ERalpha protein expression could explain the bone loss in these MIO patients.

Effect of oral isotretinoin treatment on skin androgen receptor levels in male acneic patients.

An oral daily dose (mean +/- SD, 0.75 +/- 0.05 mg/kg) of isotretinoin was administered for 3 months to six male patients with acne (scores of 4 and 5 according to Rosenfield). The therapy resulted in complete resolution of acne in four patients and improved acne significantly (score 1) in two patients. In accordance with recent findings, no change in serum testosterone and significant decreases in 5 alpha-dihydrotestosterone, 5 alpha-androstane-3 alpha,17 beta-diol glucosiduronate, and androsterone glucosiduronate levels were observed after treatment. Androgen receptor status was investigated in back skin biopsies obtained in acne areas before and after 3 months of isotretinoin treatment. The treatment did not modify the binding affinity constant of skin androgen receptor (0.44 vs. 0.32 nmol/L), but it did induce a 2.6-fold decrease in its binding capacity constant (62 vs. 24 fmol/mg cytosolic protein), as assessed by Scatchard plot and confirmed immunologically by Western blot analysis. These data clearly showed that skin androgen receptor was sensitive to oral isotretinoin administration in acneic patients. The decrease in skin androgen receptor levels (this study) and the recently reported suppression of skin 5 alpha-dihydrotestosterone production by isotretinoin treatment appeared consistent with the involvement of androgen receptor and 5 alpha-dihydrotestosterone in the pathogenesis of acne. Indeed, sebum production is under androgen control, and an abnormal response of the pilosebaceous unit to androgens appears to be implicated in the pathogenesis of acne. These observations were consistent with the absence of sebum in complete androgen-insensitive patients and normal sebum production in male pseudohermaphrodites.