Tadalafil modulates aromatase activity and androgen receptor expression in a human osteoblastic cell in vitro model.

Abstract

PURPOSE:

Phosphodiesterase type-5 inhibitor (PDE5i) tadalafil administration in men with erectile dysfunction is associated with increased testosterone/estradiol ratio, leading to hypothesize a potential increased effect of androgen action on target tissues. We aimed to characterize, in a cellular model system in vitro, the potential modulation of aromatase and sex steroid hormone receptors upon exposure to tadalafil (TAD).

METHODS:

Human osteoblast-like cells SAOS-2 were chosen as an in vitro model system since osteoblasts are target of steroid hormones. Cells were tested for viability upon TAD exposure, which increased cell proliferation. Then, cells were treated with/without TAD for several times to evaluate potential modulation in PDE5, aromatase (ARO), androgen (AR) and estrogen (ER) receptor expression.

RESULTS:

Osteoblasts express significant levels of both PDE5 mRNA and protein. Exposure of cells to increasing concentrations of TAD (10(-8)-10(-7) M) decreased PDE5 mRNA and protein expression. Also, TAD inhibited ARO mRNA and protein expression leading to an increase in testosterone levels in the supernatants. Interestingly, TAD increased total AR mRNA and protein expression and decreased ERα, with an increased ratio of AR/ER, suggesting preferential androgenic vs estrogenic pathway activation.

CONCLUSIONS:

Our results demonstrate for the first time that TAD decreases ARO expression and increases AR protein expression in human SAOS-2, strongly suggesting a new control of steroid hormones pathway by PDE5i. These findings might represent the first evidence of translational actions of PDE5i on AR, which leads to hypothesize a growing relevance of this molecule in men with prostate cancer long-term treated with TAD for sexual rehabilitation.

• Authors: A Aversa, S Fittipaldi, V M Bimonte, F Wannenes, V Papa, D Francomano, E A Greco, A Lenzi, S Migliaccio
• Journal: Journal of endocrinological investigation (J Endocrinol Invest) Vol. 39 Issue 2 Pg. 199-205 (Feb 2016) ISSN: 1720-8386 [Electronic] Italy
• PMID: 26134065 (Publication Type: Journal Article)

Chemical References

• AR protein, human
• ESR1 protein, human
• Estrogen Receptor alpha
• Phosphodiesterase 5 Inhibitors
• RNA, Messenger
• Receptors, Androgen
• Testosterone
• Tadalafil
• Aromatase
• CYP19A1 protein, human
• Cyclic Nucleotide Phosphodiesterases, Type 5
• PDE5A protein, human

Topics

• Aromatase (chemistry, genetics, metabolism)
• Carcinogenesis (chemically induced)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cyclic Nucleotide Phosphodiesterases, Type 5 (chemistry, genetics, metabolism)
• Down-Regulation (drug effects)
• Enzyme Repression (drug effects)
• Estrogen Receptor alpha (antagonists & inhibitors, genetics, metabolism)
• Humans
• Osmolar Concentration
• Osteoblasts (cytology, drug effects, metabolism)
• Phosphodiesterase 5 Inhibitors (adverse effects, pharmacology)
• RNA, Messenger (metabolism)
• Receptors, Androgen (chemistry, genetics, metabolism)
• Tadalafil (adverse effects, pharmacology)
• Testosterone (agonists, metabolism)
• Up-Regulation (drug effects)