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Testosterone replacement therapy may upregulate pro-erectile markers by modulating endothelial function In hypogonadal men with erectile dysfunction

Alzweri, L1; Gur, S2; Abdel-Mageed, AB1; Hellstrom, WJ1

1: Tulane University, United States; 2: Ankara University, Turkey

Introduction and objective: Testosterone (T) deficiency (hypogonadism) is strongly associated with erectile dysfunction (ED). The relaxant response of T on non-genomic pathways on the corporal smooth muscle has been reported. However, there is no evidence on the in vitro mediating effects of T on human corpus cavernosum (HCC). We aimed to compare the mediating effects of different T concentrations on nitric oxide (NO)-dependent & -independent nitrergic relaxations in organ bath studies.                                                                 Methods: HCC samples were obtained after consent from men undergoing penile prosthesis implantation (n = 9). After phenylephrine (Phe) contraction, electrical field stimulation (EFS), acetylcholine (ACh) and phosphodiesterase-5 (PDE-5) inhibitor (sildenafil) induced relaxation at 150, 400, and 600 ng/dL T incubations of HCC strips were performed using organ bath preparations. HCC measurements of endothelial nitric oxide synthase (eNOS), neuronal (nNOS) and PDE5 were evaluated through immunostaining, Western blotting, and cGMP and nitrite/nitrate assays.

Results: The relaxation responses to ACh and EFS in isolated HCC were significantly increased by all T levels, as compared to untreated tissues. However, sildenafil-induced relaxant responses were significantly increased at eugonadal T. The unaltered neurogenic contractions to EFS were observed. Eugonadal T levels may be accompanied by increased eNOS, nNOS and cGMP, along with lower PDE5 protein expressions. Tissue nitrate/nitrite concentration (NO production marker) was enhanced by eugonadal T levels (see Table). 

Conclusions: We provide novel data that reveal the role and importance of the short-term and modulatory effects of T incubations in HCC. Eugonadal T levels mediated HCC relaxation via downstream stimulation of nNOS, eNOS and cGMP and by inhibiting PDE5, resulting in restoring erectile function. These results suggest that T replacement therapy may upregulate erectile function by modulating endothelial function in hypogonadal men with ED, and improve the therapeutic response of PDE5i. Additional studies are required to establish the non-genomic effects of T to maintain erectile function.

     

Table 1

Untreated

Testosterone  (150 ng/dL)

 Testosterone

(400 ng/dL)

 Testosterone

(over 600 ng/dL)

% Relaxation of Phe contraction (Emax)

ACh (100µM)

46.3 ±5.6

74.5 ± 6.1*

93.7 ± 3.3***

87.0 ± 13.0**

EFS (20 Hz)

26.0 ± 5.1

44.0 ± 4.0*

56.6 ± 9.28*

28.8 ± 8.8

Sildenafil (10µM)

14.2 ± 3.7

26.5 ± 12.5

95.0 ± 2.9***

82.8 ± 9.6***

Contractile response (g/g tissue)

EFS (40Hz)

0.86 ± 0.16

0.9 ± 0.07

0.91 ± 0.07

0.78 ±0.06

cGMP (pmol.g-1)

6.21 ± 1.63

4.26 ± 2.41

26.10 ± 4.3**

31.60 ± 4.33**

NO2/NO3 (NOx, nmol/g tissue)

70.13 ± 3.26

62.6 ± 2.18

98.10 ± 5.60*

87.05 ± 26.25*

Disclosure:

Work supported by industry: no. The presenter or any of the authors act as a consultant, employee (part time or full time) or shareholder of an industry.

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