Erectile Dysfunction

Erectile dysfunction (ED) is the inability to obtain or maintain a penile erection for sexual satisfaction. The risk of ED increases with age, occurring in 40% of men aged between 40 and 70 years. The most common causes of ED are neurogenic and vascular factors, which tend to increase with age and are present in several other pathological conditions, such as hypertension, diabetes, atherosclerosis, hyperlipidemia, and metabolic syndrome. Other risk factors include obesity, smoking, depression, alcohol consumption, sedentary lifestyle, radical prostatectomy, prior pelvic surgery, and spinal cord injury. Currently, ED therapy consists of both non-invasive and invasive methods. Treatment options for ED include lifestyle changes, oral medication, penile injections, and penile implant prosthesis surgery. With the development of new innovations, some ED therapies are still in the experimental stages, such as penile shockwave therapy, stem cell injections, or platelet-rich plasma (PRP). These therapies show promising results and have the potential to become part of the ED treatment algorithm in the future (Argiolas et al., 2023; Krzastek et al., 2019). Oral medication therapy is generally recommended due to its effectiveness and safety, although it may not work for all patients and provides only temporary relief without addressing the underlying cause (Margiana et al., 2024). International guidelines for the management of ED recommend the use of phosphodiesterase 5 inhibitors (PDE5 inhibitors) as the first-line treatment due to their efficacy and safety (Wang et al., 2024). Several oral PDE5 inhibitors are used, such as Viagra (sildenafil), which can induce an erection in 80% of men with ED. Viagra works by slowly breaking down cyclic GMP (cGMP), thus increasing cGMP dilation of penile arteries and causing an erection. Other drugs like Levitra (vardenafil) and Cialis (tadalafil) have similar effects. However, these drugs have side effects such as flushing or redness and heat in the face, neck, or chest, headaches, nasal congestion, and patients taking these drugs are also advised against consuming nitroglycerin for heart disease. Patients with heart problems are not allowed to take PDE5 inhibitors (Jones & Lopez, 2014).

Potential of Stem Cell and Secretome Therapy in Erectile Dysfunction

The potential effects of stem cell and secretome therapy in the field of regenerative urology have been widely researched. The abilities of stem cells, such as self-renewal, proliferation, and differentiation into terminal cell types, are important factors in tissue or cell regeneration. Stem cells have unique effects, including pro-angiogenic, anti-fibrotic, and anti-apoptotic properties that can enhance therapeutic effects in urological diseases with limited pharmacological and surgical treatment options. In recent years, theories related to the paracrine activity of stem cells have become increasingly important, as their main effects on regeneration are better understood. Stem cells exert significant therapeutic effects through paracrine activity by collectively secreting bioactive molecules (growth factors, cytokines, and extracellular vesicles) known as secretome. This secretome consists of factors with anti-fibrotic, pro-angiogenic, and anti-apoptotic effects that play a crucial role in tissue repair and regeneration (Margiana et al., 2024). The mechanism of stem cells, particularly mesenchymal stem cells (MSCs), is believed to enable differentiation into various cell types, such as endothelial cells, smooth muscle cells, Schwann cells, and neurons. Intracavernous injection of MSCs can potentially replace damaged endothelial and/or cavernous smooth muscle cells. Additionally, some theories explain the paracrine effects of MSCs after injection. Preclinical studies in animal models have found the role of secreted factors from stem cells, such as neurotrophic factors, vascular endothelial growth factor (VEGF), and hepatocyte growth factor (HGF), in improving erectile function based on penile hemodynamics, intracavernous pressure, and mean arterial penile pressure. This indicates the ability of stem cells to regenerate damaged tissue, as well as to alter nitric oxide synthase (NOS), cGMP levels, and the smooth muscle to collagen ratio. Preclinical studies show improvements in cavernous vascular endothelial function and suppression of cavernous fibrosis by increasing smooth muscle proportion. MSCs also improve neurological function in the penile cavernous body, which is crucial for erectile function (Pérez-Aizpurua et al., 2023). The mechanism of secretome in ED models also shows potential. In a study by Kim et al., the effects of MSC secretome on a rat model with cavernous nerve injury (CNI) were observed. Results showed that MSC secretome could repair damaged cavernous tissue, thereby improving erectile function. This effect is due to angiotropic and neurotropic influences, suggesting that MSC secretome has significant potential in improving ED (Kim et al., 2022). Another study by Schwarz et al. investigated 20 patients with ED who received intracavernous injections of acellular stem cell-derived bioactive molecules. In this study, patients were given local anesthesia with 2% lidocaine before receiving intracavernous injections of acellular stem cell-derived bioactive molecules into the penile body with a total of 6 injections (0.33 cc/injection, total 2 cc) using a 22G needle. Patients were observed for 20 minutes before being discharged. They were followed up by telephone using the International Index of Erectile Function questionnaire (IIEF-5) and the Short-Form-36 questionnaire (SF-36) to assess quality of life, comparing before and 6 months after therapy. Results showed that the IIEF-5 score significantly increased in the treated group, and patient quality of life significantly improved. This indicates that a single intracavernous injection of acellular stem cell-derived bioactive molecules can improve erectile function and quality of life in ED patients (von Schwarz et al., 2021). Currently, ED treatments focus on increasing blood flow to the penis through the use of medications such as PDE5 inhibitors and intraurethral suppositories. If these measures fail, surgical implantation of penile prostheses may be necessary. The therapeutic potential of MSCs and secretome, with their ability to enhance nerve and blood vessel growth, has been demonstrated in preclinical studies using animal ED models, suggesting that MSCs may offer a promising treatment option for men suffering from ED in the future. Currently, secretome therapy research is still limited to small subject numbers, indicating a need for further studies with larger subject populations (Margiana et al., 2024).

Reference:

Argiolas, A., Argiolas, F. M., Argiolas, G., & Melis, M. R. (2023). Erectile Dysfunction: Treatments, Advances and New Therapeutic Strategies. In Brain Sciences (Vol. 13, Issue 5). MDPI. https://doi.org/10.3390/brainsci13050802

Jones, R. E., & Lopez, K. H. (2014). The Human Sexual Response. In Human Reproductive Biology (pp. 135–157). Elsevier. https://doi.org/10.1016/b978-0-12-382184-3.00008-8

Kim, S. G., You, D., Kim, K., Aum, J., Kim, Y. S., Jang, M. J., Moon, K. H., & Kang, H.-W. (2022). Therapeutic Effect of Human Mesenchymal Stem Cell-Conditioned Medium on Erectile Dysfunction. The World Journal of Men’s Health, 40(4), 653–662. https://doi.org/10.5534/wjmh.210121

Krzastek, S. C., Bopp, J., Smith, R. P., & Kovac, J. R. (2019). Recent advances in the understanding and management of erectile dysfunction. In F1000Research (Vol. 8). F1000 Research Ltd. https://doi.org/10.12688/f1000research.16576.1

Margiana, R., Pilehvar, Y., Amalia, F. L., Lestari, S. W., Supardi, S., & I’tishom, R. (2024). Mesenchymal stem cell secretome: A promising therapeutic strategy for erectile dysfunction? In Asian Journal of Urology. Editorial Office of Asian Journal of Urology. https://doi.org/10.1016/j.ajur.2024.02.003

Pérez-Aizpurua, X., Garranzo-Ibarrola, M., Simón-Rodríguez, C., García-Cardoso, J. V., Chávez-Roa, C., López-Martín, L., Tufet i Jaumot, J. J., Alonso-Román, J., Maqueda-Arellano, J., Gómez-Jordana, B., Ruiz de Castroviejo-Blanco, J., Osorio-Ospina, F., González-Enguita, C., & García-Arranz, M. (2023). Stem Cell Therapy for Erectile Dysfunction: A Step towards a Future Treatment. In Life (Vol. 13, Issue 2). MDPI. https://doi.org/10.3390/life13020502

von Schwarz, E. R., Busse, N., Angelus, K. M., Omair, A., von Schwarz, A. A., & Bogaardt, P. C. (2021). Intracavernous injection of stem cell-derived bioactive molecules for erectile dysfunction—a pilot phase non-randomized controlled trial. Journal of Men’s Health, 17(4), 99–108. https://doi.org/10.31083/jomh.2021.090

Wang, W., Liu, Y., Zhu, Z. Bin, Pang, K., Wang, J. K., Gu, J., Li, Z. B., Wang, J., Shi, Z. D., & Han, C. H. (2024). Research Advances in Stem Cell Therapy for Erectile Dysfunction. In BioDrugs (Vol. 38, Issue 3, pp. 353–367). Adis. https://doi.org/10.1007/s40259-024-00650-9