madman
Super Moderator
ABSTRACT
Introduction: Previous research in the field of cardiovascular diseases suggests a relaxing effect of testosterone (T) on smooth muscle cells. Therefore, it was hypothesized that T could play a significant role in erection development.
Aim: To investigate the relaxing effect of T and other molecules of the T signaling pathway on human corpus cavernosum (HCC) tissue.
Methods: Samples of the HCC tissue were obtained from men who underwent penile prosthesis implantation (n ¼ 33) for erectile dysfunction. Samples were used for isometric tension measurement in Ex Vivo experiments. Following standardized precontraction with phenylephrine, increasing doses of T or dihydrotestosterone were administered and blocked by NO/H2S synthesis inhibitors, a KATP blocker, and flutamide (androgen receptor inhibitor).
Main Outcome Measure: The outcome was relaxation of the HCC tissue, normalized to a maximum precontraction achieved by phenylephrine.
Results: A dose-dependent relaxing effect of dihydrotestosterone and T was observed with a relaxation of, respectively, 24.9% ± 23.4% (P < .0001) and 41.7% ± 19.1% (P ¼ .01) compared with 6.8% ± 15.9% for vehicle (dimethylsulfoxide) at 300 mM. The relaxing effect of T was not countered by blocking NO synthesis, H2S synthesis, KATP channels, or the androgen receptor.
Clinical Implications: By understanding the underlying mechanisms of T-induced HCC relaxation, potential new therapeutic targets can be identified.
Strengths & Limitations: The strength of the study is the use of fresh HCC tissues with reproducible results. The limitation is the need for supraphysiological T levels to induce the observed effect.
Conclusion: Rapid androgen-induced relaxation of HCC is likely to occur via nongenomic mechanisms. Previously suggested mechanisms of action by which T modulates HCC relaxation have been excluded.
Introduction
The physiological actions of androgens are primarily mediated through the androgen receptor (AR), which is a ligand inducible transcription factor. Upon androgen binding, the AR binds specific sites in the genome, eventually resulting in differential gene transcription and protein synthesis. Within this classical genomic model, the androgen effects cannot occur sooner than the time it takes for the steroid to trigger gene transcription followed by protein synthesis, which typically peaks several hours after steroid exposure.
Accumulating evidence, however, has shown that a nonclassical mode of androgen action exists, which at least initially is a nongenomic effect and is characterized by response times being seconds to minutes.
Multiple nongenomic modes of action have been described, with the most conserved cellular response to androgens being the rapid rise of intracellular calcium concentration, appearing within seconds to minutes upon androgen exposure. Specifically, androgens have shown to induce relaxation of the aorta and coronary arteries in a nongenomic fashion by interacting with the myocytes.
The erectile tissue of the penis consists of a ventral corpus spongiosum and 2 lateral corpora cavernosa, bordered by a dense collagenous tunica albuginea. The corpora contain irregular vascular spaces, lined by endothelium. Upon parasympathetic stimulation, the distributing arteries relax and the vascular spaces fill with blood. This leads to a distention of the corpora, pressing against the tunica albuginea, compressing the veins preventing blood to drain away. Therefore, for an erection to properly occur, adequate arterial relaxation is mandatory, which is one of the reasons (cardio)vascular diseases are an underlying cause of erectile dysfunction (ED). Based on the known effects of T on relaxation of coronary arteries, similar effects could be expected on the corporal arteries. Interestingly, comparing systemic and cavernous T levels, in healthy subjects, corporal T levels increased significantly compared with systemic T levels during erections. Based on these existing data, in this manuscript, we hypothesize that T and its derivatives play a role in the physiology of erection development and could potentially play a therapeutic role in patients with ED.
Discussion
The concentrations of T and DHT that were used to induce relaxation of HCC in this study were significantly higher than the circulating levels in adult human male plasma (10-50 nM). However, similarly, supraphysiological levels of T are necessary to induce vasorelaxation in aorta and the mesenteric artery in in vitro settings. In addition, in male patients with coronary heart disease, intravenous injection of supraphysiological doses of androgens significantly delays ST segment depression on electrocardiogram during exercise tests and dramatically induces (brachial) artery vasodilatation, while the administration of physiological levels does not result in this effect. However, upon long-term administration of physiological T levels, vasodilatory effects are observed comparable with the acute effect at supraphysiological T levels. Thus, evidence suggests that androgens applied within a physiological concentration range have a significant relaxant effect on vascular smooth musculature only after chronic exposure. The underlying cause for this phenomenon has not been elucidated yet. However, this could explain why in this experimental setup, high T levels are necessary to induce HCC tissue relaxation. Another potential reason for this observation could be inherent to the selected patient population. Changes in physiological function of the smooth muscle cells, extracellular matrix of HCC, and possibly tissue responsiveness to T are known to accompany patients suffering from ED.
*However, upon long-term administration of physiological T levels, vasodilatory effects are observed comparable with the acute effect at supraphysiological T levels. Thus, evidence suggests that androgens applied within a physiological concentration range have a significant relaxant effect on vascular smooth musculature only after chronic exposure.
CONCLUSIONS
Rapid androgen-induced relaxation of HCC is likely to occur via nongenomic mechanism in an ex vivo setting. We have excluded previously suggested mechanisms of action by which T modulates HCC relaxation. Additional studies are required to further investigate the molecular mechanism causing T-induced HCC relaxation.
Introduction: Previous research in the field of cardiovascular diseases suggests a relaxing effect of testosterone (T) on smooth muscle cells. Therefore, it was hypothesized that T could play a significant role in erection development.
Aim: To investigate the relaxing effect of T and other molecules of the T signaling pathway on human corpus cavernosum (HCC) tissue.
Methods: Samples of the HCC tissue were obtained from men who underwent penile prosthesis implantation (n ¼ 33) for erectile dysfunction. Samples were used for isometric tension measurement in Ex Vivo experiments. Following standardized precontraction with phenylephrine, increasing doses of T or dihydrotestosterone were administered and blocked by NO/H2S synthesis inhibitors, a KATP blocker, and flutamide (androgen receptor inhibitor).
Main Outcome Measure: The outcome was relaxation of the HCC tissue, normalized to a maximum precontraction achieved by phenylephrine.
Results: A dose-dependent relaxing effect of dihydrotestosterone and T was observed with a relaxation of, respectively, 24.9% ± 23.4% (P < .0001) and 41.7% ± 19.1% (P ¼ .01) compared with 6.8% ± 15.9% for vehicle (dimethylsulfoxide) at 300 mM. The relaxing effect of T was not countered by blocking NO synthesis, H2S synthesis, KATP channels, or the androgen receptor.
Clinical Implications: By understanding the underlying mechanisms of T-induced HCC relaxation, potential new therapeutic targets can be identified.
Strengths & Limitations: The strength of the study is the use of fresh HCC tissues with reproducible results. The limitation is the need for supraphysiological T levels to induce the observed effect.
Conclusion: Rapid androgen-induced relaxation of HCC is likely to occur via nongenomic mechanisms. Previously suggested mechanisms of action by which T modulates HCC relaxation have been excluded.
Introduction
The physiological actions of androgens are primarily mediated through the androgen receptor (AR), which is a ligand inducible transcription factor. Upon androgen binding, the AR binds specific sites in the genome, eventually resulting in differential gene transcription and protein synthesis. Within this classical genomic model, the androgen effects cannot occur sooner than the time it takes for the steroid to trigger gene transcription followed by protein synthesis, which typically peaks several hours after steroid exposure.
Accumulating evidence, however, has shown that a nonclassical mode of androgen action exists, which at least initially is a nongenomic effect and is characterized by response times being seconds to minutes.
Multiple nongenomic modes of action have been described, with the most conserved cellular response to androgens being the rapid rise of intracellular calcium concentration, appearing within seconds to minutes upon androgen exposure. Specifically, androgens have shown to induce relaxation of the aorta and coronary arteries in a nongenomic fashion by interacting with the myocytes.
The erectile tissue of the penis consists of a ventral corpus spongiosum and 2 lateral corpora cavernosa, bordered by a dense collagenous tunica albuginea. The corpora contain irregular vascular spaces, lined by endothelium. Upon parasympathetic stimulation, the distributing arteries relax and the vascular spaces fill with blood. This leads to a distention of the corpora, pressing against the tunica albuginea, compressing the veins preventing blood to drain away. Therefore, for an erection to properly occur, adequate arterial relaxation is mandatory, which is one of the reasons (cardio)vascular diseases are an underlying cause of erectile dysfunction (ED). Based on the known effects of T on relaxation of coronary arteries, similar effects could be expected on the corporal arteries. Interestingly, comparing systemic and cavernous T levels, in healthy subjects, corporal T levels increased significantly compared with systemic T levels during erections. Based on these existing data, in this manuscript, we hypothesize that T and its derivatives play a role in the physiology of erection development and could potentially play a therapeutic role in patients with ED.
Discussion
The concentrations of T and DHT that were used to induce relaxation of HCC in this study were significantly higher than the circulating levels in adult human male plasma (10-50 nM). However, similarly, supraphysiological levels of T are necessary to induce vasorelaxation in aorta and the mesenteric artery in in vitro settings. In addition, in male patients with coronary heart disease, intravenous injection of supraphysiological doses of androgens significantly delays ST segment depression on electrocardiogram during exercise tests and dramatically induces (brachial) artery vasodilatation, while the administration of physiological levels does not result in this effect. However, upon long-term administration of physiological T levels, vasodilatory effects are observed comparable with the acute effect at supraphysiological T levels. Thus, evidence suggests that androgens applied within a physiological concentration range have a significant relaxant effect on vascular smooth musculature only after chronic exposure. The underlying cause for this phenomenon has not been elucidated yet. However, this could explain why in this experimental setup, high T levels are necessary to induce HCC tissue relaxation. Another potential reason for this observation could be inherent to the selected patient population. Changes in physiological function of the smooth muscle cells, extracellular matrix of HCC, and possibly tissue responsiveness to T are known to accompany patients suffering from ED.
*However, upon long-term administration of physiological T levels, vasodilatory effects are observed comparable with the acute effect at supraphysiological T levels. Thus, evidence suggests that androgens applied within a physiological concentration range have a significant relaxant effect on vascular smooth musculature only after chronic exposure.
CONCLUSIONS
Rapid androgen-induced relaxation of HCC is likely to occur via nongenomic mechanism in an ex vivo setting. We have excluded previously suggested mechanisms of action by which T modulates HCC relaxation. Additional studies are required to further investigate the molecular mechanism causing T-induced HCC relaxation.
