ESWT is a widely used treatment method in the treatment of erectile dysfunction (ED, erection problem) in recent years. It is a treatment method recommended by the American Urology Association and the European Urology Association (AUA, EAU). With this method, low-intensity shock waves are delivered to the penis. Low intensity extracorporeal shock wave therapy (Li-ESWT) is also known as low intensity shock wave therapy or shock wave therapy for short. Li-ESWT is a treatment method by applying external shock waves to the penis.

There is no need for anesthesia, that is, anesthesia for the procedure. It is a painless treatment. It is sufficient to apply gel to the head that will apply the shock wave to the penis to transmit the shock currents more effectively. Patients may feel a slight tingling sensation in the applied penile part. The degree of shock waves and the number of strokes to be made in a certain time are planned according to the patient in advance. A session takes an average of 15-20 minutes.

ESWT was first used in the treatment of erectile dysfunction in 2010. It is a new technique whose effectiveness has been demonstrated by many scientific studies. In this article, I will explain how ESWT, which has been widely used in the treatment of erectile dysfunction in recent years, works (effect mechanism).

Experimental studies

There are many laboratory studies that show how ESWT works in the treatment of erectile dysfunction. The experimental animals used in these studies are normal and diseased animals. Diseases that cause erection problems similar to humans have been created in animals and the effects of ESWT on their penises have been investigated. The results obtained here provide information about how ESWT treatment to the penis is effective in humans.

Animal studies related to the application of ESWT to the penis were mostly conducted in the following groups:

• Normal experimental animals
• Elderly experimental animals
• Diabetic (diabetes) created experimental animals
• Animals with obesity
• Animals with experimental hypertension (high blood pressure).
• Experimental animals whose penile nerve was cut

Studies in cell cultures

Another way in which diseases and treatment methods are investigated non-human is cell culture studies. Such studies are called “in vitro” studies. Cell cultures are used in in vitro studies. In order to demonstrate how ESWT works, two types of cell cultures have been used in in vitro studies in the literature. These two cell cultures;

• Schwan cell culture
• HUVEC (human umblical vein endothelial cells)

Studies on the stem cell

In recent years, penile stem cell application is a treatment method applied to patients with erectile dysfunction. Stem cell application has not yet been among the routine treatment methods. It is still in the research phase. The effects of ESWT treatment on the stem cell applied penis were also investigated in laboratory animals. There are two types of stem cells commonly used for this purpose;

• Bone marrow derived stem cell
• Stem cell derived from adipose tissue

Mechanisms of action of ESWT

Laboratory animal and cell culture studies provide detailed information about the effects of ESWT on the penis. Since it is not always possible to take parts from human tissues and examine them, medical studies are primarily carried out in experimental animals and cell cultures. Then, according to the results to be obtained from these, applications are made in humans. Such studies are called “preclinical” studies. According to preclinical studies, the erection-correcting effects of ESWT application on the penis are as follows;

Vasodilation/NO (vasodilation): Vasodilation is an important mechanism in the formation of an erection. In order for an erection to occur, the veins (arteries) carrying clean blood to the penis should be widened and the veins (veins carrying dirty blood) should be closed. As a result, an erection occurs. The molecule called nitric oxide (NO) plays a very important role in vasodilation. NO is secreted by endothelial nitric oxide synthetase (e NOS) in the cavernous endothelium and neuronal nitric oxide synthetase (n NOS) in nerve endings in the penis. In cell culture studies, it has been shown that ESWT application increases e NOS and n NOS activity in the penis. And as a result, NO levels increased.

Erection problems are frequently seen in patients whose cavernous nerve (penis nerve) is cut due to diabetes (diabetes) and prostate cancer. It has been shown that ESWT application for more than 4 weeks in diabetic and bilateral cavernous nerve cut rats (rat) increases e NOS and n NOS activity and c GMP (cyclic guanosine monophosphate, a molecule related to NO release) levels in cavernous tissue. Some patients respond to ESWT as early as 1-2 days. This is due to the activation of the NO vasodilation system in the early period.

Erectile dysfunction is a common problem in the elderly. Studies in elderly laboratory animals have shown that ESWT reduces sympathetic activity in the penis (increased alpha-2 adrenergic receptors, decreased alpha-1 adrenergic receptors). As a result, smooth muscle relaxation is facilitated and thus erection occurs.

New vessel formation (neoangiogenesis): New vessel formation and regeneration of micro vessels are important in the mechanism of erection. Microvessels have been shown to be impaired in patients with erectile dysfunction. ESWT application to the penis increases the microvessel formation in the penis, ensures the regeneration of the microvessels, and affects the growth factors related to the microvessels. We can list the effects of ESWT application to the penis on microvessels as follows;

• Increase of aniogenic growth factors (increases growth factors related to vessel formation)
• Increase in the number of endothelial cells: It has been shown that there is a decrease in the endothelial cells in the cavernous tissue in experimental animals whose cavernous nerve is cut. This situation improved significantly in rats who underwent ESWT.
• Increase in capillaries (capillary increase) is seen
• Some growth factors increase within 24 after ESWT: VEGF, VEGF-A, and its receptor VEGFR-2 and angiopoietin,
• In addition, ESWT positively affects the lymphatic system.
• It has been shown to have an antiatherosclerotic effect (prevents atherosclerosis).
• It increases the release of VEGF (vascular endothelial growth factor) and endothelial cell markers such as thrombocyte and endothelial cell adhesion molecule -1 in the penis.
• In HUVEC studies, it has been shown that cells seeded in matigel form distinct tubes and connections with ESWT application.
• Increases the stem cells in the penis in animals whose penile nerve is cut and these accelerate nerve healing.
• It has been shown that when bone marrow stem cells are given and ESWT is applied to experimental animals with diabetes, there is a greater increase in erection and new vessel formation.
• ESWT provides proliferation of existing endothelial cells, stimulation of local progenitor cells or activation of circulating progenitor cells (stem cells).

Activation of progenitor cells: It has been shown that there is an increase in the number of progenitor cells (stem cells) after ESWT in many tissues. ESWT is estimated to achieve this by stimulating multiple growth factors. ESWT has been shown to increase the transformation of bone marrow-derived stem cells into endothelial and nerve cells in in vitro studies. In this way, it is estimated that it can contribute to vascular and nerve healing.

When the studies on the effects of ESWT on stem cells in the penis are examined; It was observed that progenitor cells were observed more in the penis with ESWT application in old and young people, this effect is more in young experimental animals. From these data, we can say that the stem cells in the penis are activated or collected in the penis with ESWT.

Anti-inflammatory effect and reduction of oxidative stress: In studies conducted in many tissues, proinflammatory cytokines and edema were decreased in the tissue with ESWT. These proinflammatory cytokines are; tumor necrosis factor-alpha, transforming growth factoreb1 (TGF-b1), interleukin 1a (IL-1a), IL-4, IL-6, IL-12, p70, IL13, IL-17, and interferon-gamma. ESWT also increases e NOS and n NOS, while decreasing i NOS (inducible nitric oxide synthase) expression. As a result, free radicals and tissue damage are reduced. Likewise, ESWT has been shown to reduce other oxidative stress markers.

It has been shown that advanced glycation end product receptor levels (RAGE) decrease in penile tissue after ESWT. AGE increases in diabetics and is an indicator of severe inflammation and is especially important in patients with diabetes mellitus.Nerve regeneration: The nerves of the penis must be normal for an erection to occur. ESWT application to the penis positively affects the penile nerve. It demonstrates this through different mechanisms. We can summarize the mechanisms by which ESWT application to the penis regulates nerve recovery as follows;

• Affects axonal healing positively, accelerates axonal regeneration: ESWT increases micro blood circulation around the nerve. It shows this by increasing VEGF. As a result, nerve healing is positively affected.
• Increases growth factors related to nerve development and recovery,
• Increases Schwan cell proliferation and activity. It does this by increasing growth factors related to nerve development.
• Increases n NOS expression in penile tissue.
• Administration of adipose tissue-derived stem cells and application of ESWT together increase beta-III tubulin expression in cavernous nerves in animals whose cavernous nerve is cut. This explains the mechanism of action of adipose tissue-derived stem cell and combined ESWT therapy in nerve healing.
• ESWT performs nerve regeneration directly by increasing nerve proliferation and indirectly through Schwan cells and angiogenesis.

Reduction of fibrosis/tissue remodeling: In many systems, it has been shown that ESWT application reduces tissue fibrosis and provides tissue regeneration. Similarly, ESWT contributes to regeneration of cavernous tissue and reduction in fibrosis. ESWT reduces fibrosis and tissue regeneration in the penis by the following mechanisms;

• Increases ESWT smooth muscle/collagen ratio in penile tissue
• There is an increase in elastin fibers after ESWT. As a result, penile elasticity increases,
• The TGF beta 1/smad ratio decreases, which indicates the antifungal effect of ESWT.
• Prevents changes in the penis due to obesity: In studies in which obesity was created, an increase in endothelial and smooth muscle cells and a decrease in lipid accumulation were observed after 4 weeks.

In this article, I tried to review the mechanisms of ESWT application due to penile erection problem by scanning the current literature on the subject. As can be seen, ESWT treatment is a treatment method with scientific foundations. There are many scientific studies on the subject in reputable medical journals. Average efficiency varies between 50-80%. The effectiveness of the treatment is not the same in every patient, it differs from patient to patient. The reason for this is that the factors that cause erectile dysfunction are different from patient to patient, factors such as the age and lifestyle of the patients.

In summary, it is possible to collect the effect mechanisms of ESWT-shock wave therapy to the penis under 5 main headings due to erection problem;

• Regulates circulation in the penis
• Activates stem cells in cavernous tissue
• Regulates the immune system
• Reduces fibrosis in the cavernous tissue, ensures tissue regeneration
• Regulates nerve recovery

Prof. Dr. Emin ÖZBEK

Urology Specialist