In this proof-of-concept study, we were able to confirm that RF treatment for ED is effective, safe and easily applicable. We demonstrated statistically significant improvement in all IIEF-15 domains, except for the sexual desire domain. The improvement in erectile function was prominently emphasized by the EHS scores, as at baseline only 46.4% reported an EHS score of 3 (penis is hard enough for penetration but not completely hard) while following treatment 67.8% reported an EHS score 3 and an additional 25% an EHS score of 4 (Penis is completely hard and fully rigid) while none reported an EHS score of 1 (Graph. 1).
Our interest in applying RF as external physical energy to the penis for the treatment of ED evolved from the documented beneficial results of LI-ESWT applied to the penis for ED treatment [4][10]. RF, which is routinely used in medicine, is a type of electric current between two electrodes.[11] When applied at low frequencies, it causes interactions between charged molecules and ions and creates heat within the tissue. The heat causes collagen fibers to undergo structural changes, resulting in the remolding of new collagen and elastin fibers[12] [13]. This type of low-intensity RF is currently used in the dermatology field to improve skin laxity and treat cellulite and wrinkles[14] These treatments are based on several laboratory research studies showing a statistically significant increase in collagen types I and III, consisting of newly synthesized collagen found in the histology of the human skin following RF treatment .[15]. Zelickson et al, using a bovine tendon histological and ultrastructural model of an RF application, documented dermal remodeling with new collagen regeneration[16]. In addition, rearrangements of collagen tissue were found in vaginal wall biopsies before and after RF application in postmenopausal women who were treated for stress urinary incontinence [17].
The rationale for improving erection quality by altering collagen characteristics is based on the fact that during erection, the increase in intracavernosal pressure depends, among others, on the integrity and function of the fibro-elastic components (collagen and elastin) within the sinusoids and within the TA[18].
Collagen types I and III are mainly present in the TA, interlaced with elastin fibers, and involved in the compression of the emissary veins. In addition, the corpora cavernosa contains an evident amount of collagen type IV[19]
Collagen IV is the major structural scaffold of the intracavernosal pillars which have an important role in maintaining the cylindrical shape, strength, and rigidity of the penis during erection, and they also significantly contribute to the regulation of the intracorporal pressure during erection [20][21] Collagen type IV also constitutes the scaffold of the basal membranes in the corpora cavernosa tissue, providing more flexibility and support to the vessels[22]. It is important to note that in recent years the basal membrane area has also been recognized as an important regulator of cell behavior, probably serving as an extracellular microenvironment sensor for endothelial cells[23]. At the penile level, the basal membrane may play a role in tissue and organ morphogenesis and angiogenesis. Collagen type IV is ideally suited for the incorporation of laminins, molecules that interact with receptors and regulate multiple cellular activities and signaling pathways [22]. Therefore, our assumption is that remodeling these components in both corpora and TA by application of low-intensity RF may improve and restore erectile quality.
Remodeling collagen by applying RF energy is a biological process that lasts approximately three months [23]. We documented favorable results as early as 4 weeks, which merit further discussion. However, similar early results were also reported following treatment of ED by other external energy sources such as LISWT[24]. According to Ciampa et al., the peak expression of the neovascularization response following LI-ESWT occurs as early as 4 weeks after treatment, which may be related to the nitric oxide (NO) mechanism.[25] Cavernosal NO activity may be enhanced by the direct effect of the higher temperature leading to vasodilation and increased blood flow, consequently leading to increases in penile PO2. High oxygen tension arterial levels promote the activation eNOs and nNOs (mediators involved in the erectile mechanism)[25, 26, 27].
Activation of these enzymes by increased temperature was demonstrated in several laboratory studies; Ilangovan et al. demonstrated that eNOs is induced in cultured endothelial cells when exposed to mild heat (42oC), and concluded that induced heat may upregulate NO synthase in cardiac cells [6]. Harris et al, in a Bovine aortic endothelial cells model, reported that incubation of cells for 1 h at 42oC was associated with increased eNOs activity, agonist-stimulated NO release, and a decreased vasoconstrictor response [27]. The penile hemodynamic changes in our study were verified objectively by penile FMD in all three measured parameters. Furthermore, our FMD results after RF treatment are in concert with data presented by Mamede et al using Duplex ultrasound and showing that RF energy improves hemodynamic parameters [28].
We expect to achieve a sustained effect of ED improvement similar to the reported dermal RF protocols [16], which is explained by vascular changes leading to physiological variations. The adventitial tissue that surrounds the penile arterioles responds to arterial "injury" by activating its resident progenitor cells and induces the process of collagenesis and angiogenesis [29–31]. The repeated heat caused by RF to the penis applied during the protocol we used, may induce the same “injury” effect and promote the remodeling of vascular cavernosal body components. In addition, Korshunov et al reported that the local heat dissipated by RF energy triggers endothelial cell interaction with medial and adventitial cells and may contribute to vascular remodeling[32]
Another possible mechanism for the early RF effects is the fact that heating by RF is volumetric, and a reverse thermal gradient is created, causing small amounts of transudate to accumulate in the extracellular matrix. A mild perivascular infiltrate after RF treatment has already been documented [33][16]. This natural inflammatory process could by itself trigger angiogenesis and collagenesis, but we can assume that some of the fluid remains in the extracellular matrix. Following repeated exposures to RF treatment, accumulation of extracellular fluid contributes to better compression of the draining venules against the TA inner wall during the following events of increased intracorporal pressure, clinically expressed as improved erections.
We used questionnaires for outcome assessments because some data such as severity and frequency of sexual function is better assessed in real life settings using patient reported outcomes (PROs), avoiding elaborated laboratory-based diagnostic testing [34]. Therefore, evaluation was done primarily based on PROs, leaving out nocturnal penile tumescence test, omitting a PDE5i washout period and allowing the participants to continue their routine sexual activity pattern. IIEF-15 served only in the initial evaluation of the patients as an additional tool for exclusion/inclusion of the patients. Nevertheless, due to the innovative nature of our study, and to have a better understanding of the underlying hemodynamic changes induced by RF treatment, we decided to apply the FMD test in a cohort of ten participants before and one month after completion of all RF sessions.
To the best of our knowledge, this is the first study in the English literature in which a beneficial effect of RF on ED was proven by using the contemporary ED evaluation protocols. However, our study served merely as a proof-of-concept trial. The small number of patients, lack of a sham-controlled group and short-term follow-up are its main limitations. Because collagen type III is present in the fibrous plaques of Peyronie's Disease as well as in the normal tunical tissue, a link between RF therapy and Peyronie's merits further research.[32]
Further randomized sham-controlled studies are essential to verify our preliminary results. In order to define the ideal treatment protocol and the most favorable levels of energy for optimal results.