Long-term testosterone stimulation induces hyperplasia in the guinea-pig prostate

Acosta, Stefan; Dizeyi, Nishtman; Feinstein, Ricardo; Pierzynowski, Stefan; Abrahamsson, Per‐Anders

doi:10.1038/sj.pcan.4500744

Cited by 6 publications

(5 citation statements)

References 16 publications

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“…As an established anabolic treatment, androgen supplementation has been shown to positively influence bone [ Kawano et al, 2003 ; Turner et al, 1990 ; Vanderschueren et al, 1993 ; Venken et al, 2006 ] and skeletal muscle [ Celotti and Negri Cesi, 1992 ; Herbst and Bhasin, 2004 ; Tingus and Carlsen, 1993 ; Yin et al, 2003 ]. However, therapeutic use of androgens has been limited, due to adverse side effects including significant cardiovascular events [ Basaria et al, 2010 ; Finkle et al, 2014 ; Vigen et al, 2013 ] and potential risk for prostate hyperplasia [ Acosta et al, 2004 ]. The recent development of androgen-like molecules (e.g., non-steroidal AR modulators) aims to retain the beneficial influence of androgen on skeletal muscle, while circumventing undesirable cardiovascular and prostate-related side-effects.…”

Section: Introductionmentioning

confidence: 99%

Molecular Targets of Androgen Signaling that Characterize Skeletal Muscle Recovery and Regeneration

et al. 2015

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The high regenerative capacity of adult skeletal muscle relies on a self-renewing depot of adult stem cells, termed muscle satellite cells (MSCs). Androgens, known mediators of overall body composition and specifically skeletal muscle mass, have been shown to regulate MSCs. The possible overlapping function of androgen regulation of muscle growth and MSC activation has not been carefully investigated with regards to muscle regeneration.Therefore, the aim of this study was to examine coinciding androgen-mediated genetic changes in an in vitro MSC model and clinically relevant in vivo models. A gene signature was established via microarray analysis for androgen-mediated MSC engagement and highlighted several markers including follistatin (FST), IGF-1, C-X-C chemokine receptor 4 (CXCR4), hepatocyte growth factor (HGF) and glucocorticoid receptor (GR). In an in vivo muscle atrophy model, androgen re-supplementation significantly increased muscle size and expression of IGF-1, FST, and HGF, while significantly decreasing expression of GR. Biphasic gene expression profiles over the 7-day re-supplementation period identifed temporal androgen regulation of molecular targets involved in satellite cell engagement into myogenesis. In a muscle injury model, removal of androgens resulted in delayed muscle recovery and regeneration. Modifications in the androgen signaling gene signature, along with reduced Pax7 and MyoD expression, suggested that limited MSC activation and increased inflammation contributed to the delayed regeneration. However, enhanced MSC activation in the androgen-deplete mouse injury model was driven by an androgen receptor (AR) agonist. These results provide novel in vitro and in vivo evidence describing molecular targets of androgen signaling, while also increasing support for translational use of AR agonists in skeletal muscle recovery and regeneration.

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Section: Introductionmentioning

confidence: 99%

Molecular Targets of Androgen Signaling that Characterize Skeletal Muscle Recovery and Regeneration

et al. 2015

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“…Our data, based on a functional approach, is in agreement with previous reports suggesting that prostatic NEC secretion is independent, directly or indirectly, of androgens' action. Prior studies have only demonstrated that castration or/and TES administrations do not www.nature.com/scientificreports/ alter NEC population nor their morphologic features 28,29 . Collectively, these findings led us to speculate that 5-HT production by NEC may be constant and induce a continuous inhibitory effect over prostatic growth independently of androgens.…”

Section: Discussionmentioning

confidence: 99%

Effects of testosterone replacement on serotonin levels in the prostate and plasma in a murine model of hypogonadism

Mota

Barbosa-Martins

Moura

et al. 2020

Sci Rep

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Benign prostate hyperplasia is a dysfunctional disease with an elevated prevalence. Despite the accepted impact of aging and testosterone (TES) in its pathophysiology, its aetiology remains unknown. Recent studies described that serotonin (5-HT) inhibits benign prostate growth through the modulation of the androgen receptor, in the presence of TES. Accordingly, this work aimed to determine the impact of castration and TES replacement in plasmatic and prostatic 5-HT regulation. C57BL/6 mice were submitted to surgical castration and divided into three groups, continually exposed to either vehicle or different TES doses for 14 days. Plasmatic 5-HT concentration was measured before and after castration, and after TES reintroduction. Finally, total prostatic weight and intra-prostatic 5-HT were determined in the different groups. Our results demonstrate that mice prostate exhibits high 5-HT tissue levels and that intra-prostatic total 5-HT was independent of castration or TES reintroduction, in all studied groups. Also, 5-HT plasmatic concentration significantly increased after castration and then normalized after TES administration. Our findings revealed that mice prostate has a high 5-HT content and that total prostatic 5-HT levels do not depend on androgens’ action. On the other hand, castration induced a significant increase in plasmatic 5-HT concentration, raising the hypothesis that androgens might be regulating the production of extra-prostatic 5-HT.

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“…However, there are still some controversies surrounding the initiation and progression of BPH with high or low TST (Saad et al 2011 ). Experimental and clinical studies have shown that the administration of anabolic steroid supplements stimulates the enlargement of the prostate in rats (Vargas et al 2013 ), guinea pigs (Acosta et al 2004 ), and even in bodybuilders (Kanayama et al 2008 , 2010 ).…”

Section: Introductionmentioning

confidence: 99%

Cyclooxygenase-2 activates EGFR–ERK1/2 pathway via PGE2-mediated ADAM-17 signaling in testosterone-induced benign prostatic hyperplasia

et al. 2022

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Objective and design Prostatic inflammation is the driving force in benign prostatic hyperplasia (BPH). This work investigated the potential modulatory effect of COX-2 inhibition on ADAM-17/EGFR/ERK1/2 axis. Materials or subjects Adult male Wistar rats were used. Treatment Celecoxib (10 and 20 mg/kg; i.p.) was injected i.p. daily for three weeks. Testosterone (TST) (3 mg/kg; s.c.) was used to induce BPH. Methods Prostatic inflammation and hyperplasia were assessed by organ weight and histopathology. Inflammatory mediators were measured using ELISA technique. Protein analysis was performed using western blotting and immunohistochemistry. Gene expression analysis was performed using qRT-PCR. Statistical analyses included one-way ANOVA and Tukey’s multiple comparison test. Results Testosterone-treated rats had a marked increase in COX-2, prostate weight, and index. Moreover, TST-induced COX-2 was inferred from cytoskeletal changes and was attributable to the overexpression of PGE2, NF-κB (p65), and IL-6. COX-2-derived PGE2 increased the activity of ADAM-17, TGF-α, and TNF-α. Consequently, EGFR–ERK1/2 pathway was over-activated, disrupting anti-apoptotic Bcl-2, cyclin D1, and pro-apoptotic Bax. Celecoxib reversed these effects. Conclusion COX-2 stimulates the ERK1/2 pathway via PGE2–ADAM-17-catalyzed shedding of TGF-α in testosterone-induced BPH. The results indicate a functional correlation between inflammation and hyperplasia in BPH.

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Long-term testosterone stimulation induces hyperplasia in the guinea-pig prostate

Cited by 6 publications

References 16 publications

Molecular Targets of Androgen Signaling that Characterize Skeletal Muscle Recovery and Regeneration

Molecular Targets of Androgen Signaling that Characterize Skeletal Muscle Recovery and Regeneration

Effects of testosterone replacement on serotonin levels in the prostate and plasma in a murine model of hypogonadism

Cyclooxygenase-2 activates EGFR–ERK1/2 pathway via PGE2-mediated ADAM-17 signaling in testosterone-induced benign prostatic hyperplasia

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