In recent years, mesenchymal stem cell (MSC) therapy has been used in the treatment of many diseases. Many of these are at the experimental stage and have not entered routine clinical practice. Stem cell studies are also available in most of the urological diseases. Erectile dysfunction is the most studied subject among urological diseases.

In recent years, there has been an increase in experimental and clinical studies on stem cell secretome. Positive results have been obtained with stem cell secretome in experimental ED models. There are also clinical studies on stem cell secretome in patients with erectile dysfunction. In these studies, no adverse side effects of secretome treatment applied to the penis were reported. Success rates were also found to be high. One of the most important advantages of secretome treatment compared to direct stem cell treatment is that the procedure takes a shorter time to be applied. There is no need for long protocols for special permissions as in stem cell therapy. In this article, I will give information about the application of stem cell secretome to the penis in patients with erectile dysfunction.

What is erectile dysfunction?

Erectile dysfunction (ED, impotence) is the inability to achieve or maintain an erection for an adequate sexual intercourse. It occurs due to many reasons. Most of them are organic. Appropriate treatment is given according to the cause and the degree of ED.

There are many studies on the efficacy of stem cell therapy in the treatment of ED. Most of these are experimental studies. The efficacy of penile stem cell therapy in different ED models has been investigated. The results obtained in the studies are generally positive. Serious side effects have not been reported. Human studies are also available. In human studies, a great deal of success has been achieved in patients with ED due to different causes. There is no common protocol in all of these studies. Different doses and treatment protocols have been used in different studies.

Structural changes that cause ED

Most of the causes of erectile dysfunction today are of organic origin. We can summarize the structural changes that occur as a result of organic ED, which develops due to various reasons, as follows:

• Changes in the cavernous artery
• Structural changes in penile smooth muscles
• Endothelial damage
• Structural changes in the tunica albuginea
• Depressions in neurotransmitter release

Stem cell use in ED treatment

When administered, stem cells transform into different cells in the human body and play an important role in the repair of damaged tissue. Stem cells applied to the penis show their effects by regenerating the damaged structures responsible for erection. They repair damaged tissues by acting mainly on the penile muscle and vascular structure.

• Ensuring the regeneration of damaged tissues
• Improving penile blood flow
• To ensure the formation of new vessels

Which stem cells are used in the treatment of ED?

Stem cells can be obtained from different tissues. When we examine the stem cells used in the literature, we see that they are obtained from the following three main sources:

• Adipose tissue-derived stem cells (ADSC)
• Bone marrow derived stem cells (BMDSC)
• Stem cells obtained from umbilical cord (UCSC)

There are some handicaps in stem cell treatment

There has been intense research on stem cell therapy in recent years. Stem cell therapy is promising in the treatment of many diseases. This new form of treatment is not yet an established treatment. Exact protocols have not been determined. There are some conditions that make stem cell therapy difficult to use widely and easily. We can list them as follows:

• Appropriate stem cell selection and injection into the penis: It must be suitable for the renewal of anatomical formations (smooth muscle, endothelial cells) in the penile structure.
• Isolation of stem cells is a long and difficult process: It requires a special team and infrastructure.
• It must be propagated in culture environments: For this, trained personnel and appropriate laboratory conditions must be provided.
• Expensive: Application is an expensive method.
• Requires a special team and infrastructure
• Appropriate dosage is very important: Since it is a new form of treatment, there are no standard doses yet for the treatment of diseases. For this, clinical studies conducted over a longer period of time and with a larger number of patients are needed.
• There is no optimal dose for maximum effectiveness
• There is no standardized protocol
• Side effects such as allergic reactions may occur.
• Stem cells may have other possible serious complications (such as malignancy).
• Treatment duration is not standard
• Their effectiveness varies from patient to patient

What is stem cell secretome?

They are substances produced by stem cells in the culture environment and released out of the cell. Stem cells are propagated in special media (culture media). These media are called “conditioned media” (secretome). There are many biologically active molecules in the culture fluid (conditioned medium, medium fluid, secrotome) in which these mesenchymal stem cells (MSC) are found. These active molecules, secretotomes, are used in the treatment of many diseases. Secretomes exert their effects through tissue-specific paracrine mechanisms. Biologically active molecules produced by stem cells are: Exosome, growth factors (growth factors), cytokines, proteins, peptides, miRNA (micro RNA).

Exosome: Exosomes are extracellular vesicles originating from the cell membrane. Exosomes do not contain cells, have no toxic effects, and are stable structures since the active substance is in the lipid cell membrane. They have high effectiveness for rejuvenation and regeneration. Exosomes have many functions as follows:

• Intercellular communication and transport of macromolecules (protein, lipid, miRNA, DNA)
• It has effects on the functions of neighboring cells
• They do not create an immune system response

Growth factors: Growth factors are signaling molecules that are naturally produced by cells and have many functions. They play an important role in cell growth, proliferation, healing and differentiation. Structurally, they are protein or steroid hormone structures. They play an important role in providing many cellular functions. Exosomes contain many growth factors.

There are three types of growth factors effective in the treatment of erectile dysfunction:

• IGF-1 (insulin-like growth factor)
• VEGF (Vascular endothelial growth factor)
• bFGF (Basic fibroblast growth factor)
• GF complex is obtained using recombinant DNA technology.

Cytokines: They are molecules in protein and peptide structure that are produced by cells and play a role in intercellular communication. They show their effects by binding to cell surfaces, play an important role in the immune system and immune response, and are not stored in the body. Anti-inflammatory cytokines found in exosomes: IL-1Ra, BDNF, CTNF.

Proteins: There are more than 190 proteins in the secretome. Proteins have many functions in the body. We can summarize these functions as follows:

• Wound healing
• Anti-inflammatory effect
• Antiapoptotic effect
• Anti aging effect
• Proliferative effect

miRNA (micro RNA): miRNA are single-stranded RNA molecules that are 21-23 nucleotides long. There is a lot of scientific research done in this field. They play a role in regulating gene expression. They are encoded by genes that cannot be translated into protein, and they control the conversion into protein by binding to mRNA. There are more than 51 miRNAs in the exosome. These show anti-inflammatory, anti-aging and proliferative effects.

How is the stem cell secretome obtained?

In order to obtain a stem cell sacrotome, laboratory environments with advanced technologies and trained personnel are needed. It is a costly process. Fat tissue is obtained from healthy volunteers who have passed all the necessary tests. Mesenchymal stem cells (MSC) are isolated, and the resulting cells are retested for endotoxin and verus. Finally, a stem cell bank is created with mesenchymal cells. Then, the stem cells are multiplied in the appropriate culture medium, the stem cells, medium and protein residues are cleaned, and finally, a pure stem cell sacrotome is obtained. The resulting secrotome is lyophilized. After that, it is presented to the markets in special packaging that can be used commercially.

Urological diseases that can be treated using stem cell secretome

Stem cells are widely used in Regenerative Urology. Most of them are still at the experimental stage. Stem cell secretosome may be effective in treating the following urological diseases:

• Stress urinary incontinence
• Kidney diseases
• Bladder dysfunctions
• Erectile dysfunction
• Peyronie’s disease

What are the advantages of stem cell secretome?

Secretomas are stem cell products. Using stem cell secretome has many advantages over using direct stem cells:

• Contains no cells
• Provides restoration of cavernous tissue thanks to the growth factors it contains.
• It is anti-inflammatory and anti-apoptotic.
• Increases the release of eNOS and nNOS (neurotransmitter responsible for erection) in the cavernous tissue.
• Regulates cavernous endothelial functions
• Cavernous smooth muscle regeneration and function regulation
• Regulates cavernous microcirculation
• Helps nerve regeneration
• It is rich in active molecules released by stem cells into the culture medium.
• Easy to use
• Since it does not contain cells, there is no need for special protocols for application
• It is cheaper than stem cell therapy
• There are no possible complications that can be seen in stem cell treatment
• It is cheaper than stem cell therapy
• Since it does not contain stem cells, there is no risk of allergic reaction, no autoimmune response

What is the cost/price of secretoma treatment?

The price (fee) of erectile dysfunction treatment with stem cell secretome is not fixed. It varies from patient to patient. Many factors such as patient-related factors, degree of erection, and patient age affect the cost. The dose used and the number of sessions also vary depending on the severity of ED.

What is the application method and protocol?

The application is made by injection into the penis. The secretome, prepared sterilely, is applied to the penis, into the cavernous tissue, with a thin needle. The procedure is painless, does not require anesthesia, and is performed in office conditions following skin cleansing.

The use of stem cell secretome in patients with erection problems is not yet a widespread treatment method. The dose and duration of treatment of this treatment method vary according to the patient. Factors such as the patient’s age, presence or absence of a chronic disease, and degree of ED are important in determining doses and dose intervals. We divide the patients into 3 main groups according to these criteria and arrange their treatments accordingly.

• Group 1 patients: Treatment in patients who are young, newly diagnosed, have no chronic disease and do not have lifestyle risk factors:

It is applied in two sessions, two weeks apart.

On demand in maintenance therapy. Another session is applied every 6-12 months.

• Group 2 patients: Treatment in patients who are elderly, previously diagnosed with ED, have accompanying chronic disease and have a normal lifestyle:

4 sessions in total, two weeks apart

In maintenance therapy, it is repeated every 6 months.

• Group 3 patients: Treatment in patients who are elderly, previously diagnosed with ED, have a chronic disease and have a risky lifestyle:

A total of 6 sessions are applied, 4 sessions with 1 week intervals and 2 sessions with 2 weeks apart.

In maintenance treatment, 2 sessions are applied in 6 months.

In summary: Secretome therapy is one of the new molecular treatment methods used in the treatment of many diseases. It is also used in the treatment of erectile dysfunction and the results are generally promising. Secretomes are biologically active molecules produced by stem cells in culture. Secretoma treatment containing these molecules prepared with special methods does not contain stem cells. The absence of stem cells in this treatment method is an advantage. It has the advantage of being ready-made and easily applied. Since it does not contain stem cells, there is no need for a special protocol and permission for the application. The dose and duration of treatment vary according to the degree of the disease and the coexisting chronic disease.

Current literature on stem cell secretoma-ED therapy

• Therapeutic Effect of Human Mesenchymal Stem Cell-conditioned Medium on Erectile Dysfunction. World J Mens Health. 2022. 
• Efficacy of a cultured conditioned medium of exfoliated deciduous dental pulp stem cells in erectile dysfunction patients. J Cell Mol Med. 2022;26(1):195-201.
• Administration of secretome from human placental stem cell-conditioned media improves recovery of erectile function in the pelvic neurovascular injury model. J Tissue Eng Regen Med. 2020;14(10):1394-1402
• Comparison of the therapeutic effects of human umbilical cord blood-derived mesenchymal stem cells and adipose-derived stem cells on erectile dysfunction in a rat model of bilateral cavernous nerve injury. Front Bioeng Biotechnol. 2022 ;10:1019063. 
• Extracellular Vesicles From Human Urine- Derived Stem Cells Ameliorate Erectile Dysfunction in a Diabetic Rat Model by Delivering Proangiogenic MicroRNA. Sex Med. 2019;7(2):241-250.
• Neurotrophic effect of bone marrow mesenchymal stem cells for erectile dysfunction in diabetic rats. Int J Androl. 2012 Aug;35(4):601-7.
• Adipose-derived stem cells improve erectile function partially through the secretion of IGF-1, bFGF, and VEGF in aged rats. Andrology. 2018 ;6(3):498-509. 
• Transdifferentiation of rat fetal brain stem cells into penile smooth muscle cells. BJU Int. 2009;104(2):257-62.
• Transplantation of induced pluripotent stem cell-derived mesenchymal stem cells improved erectile dysfunction induced by cavernous nerve injury. Theranostics. 2019;14;9(22):6354-6368.
• Transplantation of adipose tissue-derived stem cell-derived exosomes ameliorates erectile function in diabetic rats. Andrologia. 2018;50(2).
• Delivery of human mesenchymal adipose-derived stem cells restores multiple urological dysfunctions in a rat model mimicking radical prostatectomy damages through tissue-specific paracrine mechanisms. Stem Cells. 2016;34(2):392-404.
• Intracavernous injection of stem cell-derived bioactive molecules for erectile dysfunction—a pilot phase non-randomized controlled trial. J. Mens. Health 2021, 17(4), 99–108

Prof. Dr. Emin ÖZBEK

Urology Specialist

Istanbul- TURKEY