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

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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.

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Acknowledgments

Research was funded by PRIN 2011 052013 to SM, PON 01_00829 to AL. FW is supported by an ELI Lilly grant. LiSa laboratories are a Joint-Venture between Eli Lilly Firenze and Sapienza University of Rome, Department of Experimental Medicine, Section of Medical Pathophysiology, Endocrinology and Nutrition, Sapienza University of Rome. AA designed the study, analyzed the in vitro data, contributed to the interpretation, wrote the manuscript, contributed to the discussion; FW, VMB, SF, VP designed the study, produced and analyzed the in vitro data, contributed to the interpretation; DF, EAG, CC contributed to the interpretation of the data and discussion, revised the manuscript; AL designed the study, reviewed the manuscript; SM, designed the study, analyzed the in vitro data, contributed to the interpretation and discussion, wrote the manuscript.

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    Authors and Affiliations

    1. Section of Medical Pathophysiology, Endocrinology and Nutrition, Department of Experimental Medicine, “Sapienza” University of Rome, Rome, Italy

      A. Aversa, D. Francomano, E. A. Greco & A. Lenzi

    2. Lisa Laboratory, Policlinico of Catania, University of Catania, Catania, Italy

      A. Aversa, S. Fittipaldi, V. M. Bimonte, F. Wannenes, V. Papa & E. A. Greco

    3. Section of Health Sciences, Department of Movement, Human and Health Sciences, “Foro Italico” University of Rome, Largo Lauro De Bosis 15, 00195, Rome, Italy

      S. Fittipaldi, V. M. Bimonte, F. Wannenes, V. Papa & S. Migliaccio

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    1. A. Aversa
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    Correspondence to A. Aversa.

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    The study in object has been approved by the local ethical committee of Sapienza University of Rome; Compliant with the Ethical standards.

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    Aversa, A., Fittipaldi, S., Bimonte, V.M. et al. Tadalafil modulates aromatase activity and androgen receptor expression in a human osteoblastic cell in vitro model. J Endocrinol Invest 39, 199–205 (2016). https://doi.org/10.1007/s40618-015-0344-1

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