scholarly journals Cytosolic androgen receptor in regenerating rat levator ani muscle

1981 ◽  
Vol 200 (1) ◽  
pp. 77-82 ◽  
Author(s):  
S R Max ◽  
S Mufti ◽  
B M Carlson
Keyword(s):  
Androgen Receptor ◽  
Striated Muscle ◽  
Fold Increase ◽  
Levator Ani ◽  
Muscle Fibres ◽  
Morphological Development ◽  
Levator Ani Muscle ◽  
Binding Characteristics ◽  
Crush Lesion ◽  
Androgen Binding

The development of the cytosolic androgen receptor was studied after degeneration and regeneration of the rat levator ani muscle after a crush lesion. Muscle regeneration appears to recapitulate myogenesis in many respects. It therefore provides a model tissue in sufficiently in large quantity for investigating the ontogenesis of the androgen receptor. The receptor in the cytosol of the normal levator ani muscle has binding characteristics similar to those of the cytosolic receptor in other androgen-sensitive tissues. By day 3 after a crush lesion of the levator ani muscle, androgen binding decreased to 25% of control values. This decrease was followed by a 4-5 fold increase in hormone binding, which attained control values by day 7 after crush. Androgen binding remained stable at the control value up to day 60 after crushing. These results were correlated with the morphological development of the regenerating muscle after crushing. It is concluded that there is little, if any, androgen receptor present in the early myoblastic stages of regeneration; rather, synthesis of the receptor may occur after the fusion of myoblasts and during the differentiation of myotubes into cross-striated muscle fibres.

Estrogen, Progesterone, and Androgen Receptor Expression in Levator Ani Muscle and Fascia

2001 ◽  
Vol 10 (8) ◽  
pp. 785-795 ◽  
Author(s):  
Pleas Copas ◽  
Antonin Bukovsky ◽  
Bridgett Asbury ◽  
Robert F. Elder ◽  
Michael R. Caudle
Keyword(s):  
Androgen Receptor ◽  
Levator Ani ◽  
Receptor Expression ◽  
Androgen Receptor Expression ◽  
Levator Ani Muscle

scholarly journals Steroidal Androgens and Nonsteroidal, Tissue-Selective Androgen Receptor Modulator, S-22, Regulate Androgen Receptor Function through Distinct Genomic and Nongenomic Signaling Pathways

2008 ◽  
Vol 22 (11) ◽  
pp. 2448-2465 ◽  
Author(s):  
Ramesh Narayanan ◽  
Christopher C. Coss ◽  
Muralimohan Yepuru ◽  
Jeffrey D. Kearbey ◽  
Duane D. Miller ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Levator Ani ◽  
Reproductive Organs ◽  
Cross Reactivity ◽  
Levator Ani Muscle ◽  
Xenopus Laevis Oocyte ◽  
Muscle Weight

Abstract Androgen receptor (AR) ligands are important for the development and function of several tissues and organs. However, the poor oral bioavailability, pharmacokinetic properties, and receptor cross-reactivity of testosterone, coupled with side effects, place limits on its clinical use. Selective AR modulators (SARMs) elicit anabolic effects in muscle and bone, sparing reproductive organs like the prostate. However, molecular mechanisms underlying the tissue selectivity remain ambiguous. We performed a variety of in vitro studies to compare and define the molecular mechanisms of an aryl propionamide SARM, S-22, as compared with dihydrotestosterone (DHT). Studies indicated that S-22 increased levator ani muscle weight but decreased the size of prostate in rats. Analysis of the upstream intracellular signaling events indicated that S-22 and DHT mediated their actions through distinct pathways. Modulation of these pathways altered the recruitment of AR and its cofactors to the PSA enhancer in a ligand-dependent fashion. In addition, S-22 induced Xenopus laevis oocyte maturation and rapid phosphorylation of several kinases, through pathways distinct from steroids. These studies reveal novel differences in the molecular mechanisms by which S-22, a nonsteroidal SARM, and DHT mediate their pharmacological effects.

Androgen-binding proteins in sheep epididymis: age-related effects on androgen-binding protein, cytosolic androgen receptor and testosterone concentrations. Correlations with histological studies

1984 ◽  
Vol 103 (3) ◽  
pp. 281-NP ◽  
Author(s):  
S. Carreau ◽  
M. A. Drosdowsky ◽  
M. Courot
Keyword(s):  
Androgen Receptor ◽  
Specific Binding ◽  
Binding Protein ◽  
Physiological Role ◽  
Fold Increase ◽  
Plasma Testosterone ◽  
Histological Studies ◽  
Age Related ◽  
Androgen Binding Protein ◽  
Androgen Binding

ABSTRACT The androgen-binding protein (ABP) and the cytosol androgen receptor (Rc) were measured in the epididymis of sheep aged 50, 120 and 200 days. Specific binding protein was not detected at 50 days (infantile); near puberty (120 days), ABP was more concentrated in caput and cauda epididymal cytosols (117 and 183 fmol/mg protein respectively) than in corpus (53 fmol/mg) although Rc levels were low (3–5 fmol/mg). In postpubertal rams (200 days), ABP and Rc concentrations were higher in caput and cauda than in corpus epididymis. Testosterone concentrations at 50 days were not statistically different along the epididymis and varied from 0·3 to 0·8 pmol/mg protein. In 120-day-old animals, testosterone was more concentrated in caput and corpus (0·45 and 0·41 pmol/mg) than in cauda (0·17 pmol/mg); at 200 days, the testosterone contents were low (0·10–0·17 pmol/mg) in all parts of the epididymis. A ten-fold increase in plasma testosterone concentrations was observed between 50 and 200 days (1·31 to 11·71 nmol/l). Histological studies of the epididymis in the three groups of animals showed that the cell differentiation started in the cauda where the principal epithelial cells were higher (47–56 μm) than in the caput (31–38 μm) at 50 days. The principal cells of the caput were two- to threefold higher in postpubertal rams than in infantile lambs, a finding which is correlated with the levels of ABP and Rc. This may suggest an important physiological role of this region in the induction of sperm maturation. J. Endocr. (1984) 103, 281–286

scholarly journals Preclinical Characterization of a (S)-N-(4-Cyano-3-Trifluoromethyl-Phenyl)-3-(3-Fluoro, 4-Chlorophenoxy)-2-Hydroxy-2-Methyl-Propanamide: A Selective Androgen Receptor Modulator for Hormonal Male Contraception

Endocrinology ◽  
2008 ◽  
Vol 150 (1) ◽  
pp. 385-395 ◽  
Author(s):  
Amanda Jones ◽  
Jiyun Chen ◽  
Dong Jin Hwang ◽  
Duane D. Miller ◽  
James T. Dalton
Keyword(s):  
Androgen Receptor ◽  
Levator Ani ◽  
Male Rats ◽  
Male Contraception ◽  
Levator Ani Muscle ◽  
Dependent Manner ◽  
Mineral Density ◽  
Intact Male ◽  
Selective Androgen Receptor Modulator ◽  
Receptor Modulator

The pharmacologic effects of (S)-N-(4-cyano-3-trifluoromethyl-phenyl)-3-(3-fluoro, 4-chlorophenoxy)-2-hydroxy-2-methyl-propanamide (S-23) were characterized in male rats as an animal model of hormonal male contraception. S-23 showed high binding affinity (inhibitory constant = 1.7 ± 0.2 nm) and was identified as a full agonist in vitro. In castrated male rats, the ED50 of S-23 in the prostate and levator ani muscle was 0.43 and 0.079 mg/d, respectively. In intact male rats treated for 14 d, S-23 alone suppressed LH levels by greater than 50% at doses greater than 0.1 mg/d, with corresponding decreases in the size of the prostate but increases in the size of levator ani muscle. In intact male rats treated for up to 10 wk with S-23 and estradiol benzoate (EB; necessary to maintain sexual behavior in rats), S-23 showed biphasic effects on androgenic tissues and spermatogenesis by suppressing serum concentrations of LH and FSH. EB alone showed no effect on spermatogenesis. In the EB + S-23 (0.1 mg/d) group, four of six animals showed no sperm in the testis and zero pregnancies (none of six) in mating trials. After termination of treatment, infertility was fully reversible, with a 100% pregnancy rate observed after 100 d of recovery. S-23 increased bone mineral density and lean mass but reduced fat mass in a dose-dependent manner. This is the first study to show that a selective androgen receptor modulator combined with EB is an effective and reversible regimen for hormonal male contraception in rats. The beneficial effects of S-23 on the muscle, tissue selectivity, and favorable pharmacokinetic properties make it a strong candidate for use in oral male contraception. An aryl-propionamide selective androgen receptor modulator (S-23) is an effective and reversible agent for hormonal male contraception in rats.

scholarly journals A Novel Mutation in the Human Androgen Receptor Suggests a Regulatory Role for the Hinge Region in Amino-Terminal and Carboxy-Terminal Interactions

2008 ◽  
Vol 93 (10) ◽  
pp. 3691-3696 ◽  
Author(s):  
A. Deeb ◽  
J. Jääskeläinen ◽  
M. Dattani ◽  
H. C. Whitaker ◽  
C. Costigan ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Nuclear Localization ◽  
Novel Mutation ◽  
Poor Response ◽  
Fold Increase ◽  
Hinge Region ◽  
Regulatory Role ◽  
Amino Terminal ◽  
Androgen Binding

Context: The androgen insensitivity syndrome (AIS) is caused by molecular defects in the androgen receptor (AR). Clinically, the partial AIS has a variable phenotype. Many mechanisms explain the phenotype in the AIS. A crucial step in AR action is the interaction of the N and C termini. Objective: The role of the hinge region of the AR is not as well understood as other parts of the receptor. We aim to study the role of this region in the N/C-termini interaction. Patient and Method: We report a patient with severe undermasculinization and poor response to exogenous androgens. Androgen binding was performed, and the AR gene was sequenced. The mutation was recreated and transfected in COS-1 cells. Transactivation was studied. N/C-termini interaction was studied using a mammalian two-hybrid assay. A nuclear localization study was performed. Results: Androgen binding was normal, and a novel mutation (Arg629Trp) in the AR hinge region was identified. Mutant AR transactivation was 40% higher compared with wild type (WT). A 3-fold increase in transcription occurred when both WT N and C-terminal domains were cotransfected; no response occurred when the mutated region of the AR was included (P < 0.001). Cells with mutant AR showed a comparable nuclear localization to the WT AR. Conclusions: A mutation in the hinge region impaired N/C-domain interaction in the presence of normal AR binding and nuclear localization. It resulted in severe undermasculinization at birth and resistance to androgens. The findings confirm a unique regulatory role for the hinge region in AR function.

Effects of castration and androgen treatment on androgen-receptor levels in rat skeletal muscles

1999 ◽  
Vol 87 (6) ◽  
pp. 2016-2019 ◽  
Author(s):  
Jose Antonio ◽  
Jean D. Wilson ◽  
Fredrick W. George
Keyword(s):  
Skeletal Muscle ◽  
Androgen Receptor ◽  
Muscle Mass ◽  
Skeletal Muscles ◽  
Skeletal Muscle Mass ◽  
Levator Ani ◽  
Male Rats ◽  
Levator Ani Muscle ◽  
Plantaris Muscle ◽  
Androgen Treatment

The effects of castration and dihydrotestosterone (DHT) treatment on levels of skeletal muscle androgen receptor (AR) were examined in three groups of adult male rats: 1) intact normal rats, 2) rats castrated at 16 wk of age, and 3) rats castrated at 16 wk of age and given DHT for 1 wk starting at week 17. All animals were killed at 18 wk of age. Castration caused a decrease ( P< 0.05) in the weights of the levator ani and bulbocavernosus muscles. The administration of DHT to the castrated rats increased ( P < 0.05) the weights of the levator ani and bulbocavernosus muscles. Castration caused a significant downregulation of AR levels in the bulbocavernosus ( P< 0.05) but had no significant effect on AR levels in the levator ani muscle. DHT administration to the castrated group upregulated AR levels in the bulbocavernosus and levator ani muscles. The plantaris muscle did not significantly ( P > 0.05) change for any of the treatments. These findings suggest that the effects of castration and androgen replacement differentially affect skeletal muscle mass and AR levels.

scholarly journals Comparison of the Pharmacological Effects of a Novel Selective Androgen Receptor Modulator, the 5α-Reductase Inhibitor Finasteride, and the Antiandrogen Hydroxyflutamide in Intact Rats: New Approach for Benign Prostate Hyperplasia

Endocrinology ◽  
2004 ◽  
Vol 145 (12) ◽  
pp. 5420-5428 ◽  
Author(s):  
Wenqing Gao ◽  
Jeffrey D. Kearbey ◽  
Vipin A. Nair ◽  
Kiwon Chung ◽  
A. F. Parlow ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Partial Agonist ◽  
Levator Ani ◽  
Male Rats ◽  
Levator Ani Muscle ◽  
Intact Male ◽  
Prostate Hyperplasia ◽  
Tissue Selectivity ◽  
Benign Prostate ◽  
Intact Rats

Abstract Tissue-selective androgen receptor modulators (SARMs) demonstrate tissue selectivity in both castrated and intact male rats, behaving as partial agonists in androgenic tissues (i.e. prostate and seminal vesicle), but full agonists in anabolic tissues (i.e. levator ani muscle). The partial agonist activity of SARMs (compounds S-1 and S-4) in the prostate of intact rats suggested that SARM could be used for androgen suppression in the treatment of benign prostate hyperplasia (BPH). This study was designed to explore the mechanisms of action of SARM and to characterize the tissue selectivity of S-1 in intact male rats compared with that of hydroxyflutamide (antiandrogen) and finasteride (5α-reductase inhibitor), two major drugs used for androgen suppression treatment of BPH. In intact male rats, S-1 (5, 10, and 25 mg/kg) selectively decreased the prostate weight with similar efficacy to finasteride (5 mg/kg), without affecting the levator ani muscle or increasing the plasma levels of testosterone, LH, and FSH. Hydroxyflutamide (0.5, 1, 5, 10, and 25 mg/kg), however, decreased both the prostate and levator ani muscle weights without any selectivity and increased plasma hormone levels in a dose-dependent manner. Furthermore, S-1 and S-4 showed very weak inhibitory effects toward transiently expressed type I and II human 5α-reductase (Ki, &gt;20 μm) during in vitro assays. Therefore, although S-1 and finasteride showed very similar suppressive effects in the prostate of intact male rats, they decreased prostate size via different mechanisms of action. S-1 simply worked as androgen receptor partial agonist, whereas finasteride inhibited prostatic 5α-reductase. These studies indicate that SARMs may demonstrate clinical utility as single agent or combination therapy for BPH.

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