This article reviews the current status of the ongoing research aiming to find a curative, rather than a symptomatic, treatment option for erectile dysfunction
Naside Mangır MD FEBU
Clinical Research Fellow, Department of Materials Science Engineering, Department of Urology, University of Sheffield, UK
Email: [email protected]
Erectile dysfunction (ED) is the persistent inability to attain and maintain an erection sufficient to permit satisfactory sexual performance.1 Other than being an early warning sign of an underlying coronary artery disease, it is a benign disorder that can have a significant impact on quality of life (QoL) of the patients and their partners, affecting the physical and psychosocial wellbeing of the sufferers.
ED is highly prevalent affecting almost 50% of male population aged 40–70 years, the figures changing with the definition of ED, the methodology of the study and the cultural and socioeconomic status of population studied.
The majority of ED cases are secondary to vascular diseases associated with smoking, ageing, hyperlipidaemia, diabetes and hypertension. Neurogenic ED due to cavernous nerve injury during pelvic surgery such as radical prostatectomy is also prevalent. Other causes of ED include trauma to external genitalia (for example, penile fracture), hormonal diseases (for example, hyperprolactinaemia, hypogonadism), psychogenic disorders (for example, lack of arousability) or drug-related (for example, antihypertensives, antidepressants).
Because ED is a symptom, not a disease, the first step in the management of ED is the determination of underlying aetiology. Yet only a small proportion of ED patients are found to have a curable or reversible underlying causes such as certain endocrinopathies and vascular injuries secondary to trauma.
The treatment of ED has been revolutionised by phosphodiesterase type 5 inhibitors (PDE5-Is). Their mechanism of action involves increasing the amount of cGMP in the corpus cavernousal tissue, which results in smooth muscle relaxation with increased arterial blood flow, leading to compression of subtunical venous plexus and penile erection and currently four potent selective PDE5-Is (sildenafil, tadalafil, vardenafil and avanafil) are approved by the European Medicines Agency.
While oral pharmacotherapy with PDE5-Is is very effective and reasonably safe with minimal adverse effects, they do not interfere with the underlying pathophysiologic mechanisms of ED. Thus the majority of ED patients rely on these drugs in order to maintain their sexual functions, which is associated with high costs. Furthermore a subgroup of ED patients can have extensive tissue damage that their response to oral or local pharmacotherapy is inadequate.
Consequently the need to find a curative, rather than a symptomatic, treatment option for ED has been recognised by the scientific community and increasing amounts of research have been published within the last few years. Therapeutic strategies like stem cell and gene therapies, low-intensity extracorporeal shock wave therapy (LI-ESWT) and long-term daily use of PDE5-Is are currently under investigation and they seem to be the most promising candidates for future therapies.
Stem cell therapy alone or in combination with other pharmacological agents has demonstrated very promising results in experimental and a few clinical studies. To date, human mesenchymal stem cells (MSCs) have been isolated from a large number of adult tissues (bone marrow, adipose tissue, skeletal muscle, etc.) and among these, adipose tissue being a rich and easily obtainable source of MSCs, has been of particular interest in treatment of ED.2
By definition MSCs are capable of self-renewal and differentiation into various phenotypes thus they can promote endothelial, smooth muscle or neural cell regeneration after transplantation into the corpus cavernosum. Also MSCs exert immunomodulatory, proangiogenic, anti-apoptotic, anti-fibrotic and anti-inflammatory effects mainly via secretion of bioactive trophic factors.3,4 The latter is suggested as the main mechanism underlying the beneficial effects observed after injection of MSCs into the corpus cavernosum.
Very recently the results of two Phase I clinical studies evaluating MSCs in the treatment of post prostatectomy ED has been published. Both studies confirmed the safety of autologous MSC therapy and a potential benefit on erectile functions.5,6 Although far from being a standard treatment in the near future, there is a great hope among researchers worldwide that in the next few years we will be able to cure ED with MSCs, at least in those patients who are not responding to standard first-line therapy with PDE5-Is.7
Extracorporeal shockwave lithotripsy (ESWL) has been safely and effectively used for the minimally invasive treatment of urinary tract stones since the 1980s. It has also been studied in other medical conditions including ischaemic heart disease, Peyronie disease, orthopaedic soft tissue diseases (for example, plantar fasciitis), however much debate surrounds these clinical applications. Recently accumulated data suggests that LI-ESWT of the corpora cavernosa can be effective in permanently improving erectile functions.
The proposed mechanism of action in all of these conditions are common and involves increased neovascularisation, direct stimulation of tissue healing and induction of an inflammatory response by the shockwaves.
In the first randomised controlled trial, LI-ESWT was shown to improve erectile functions in 20 males with vasculogenic ED and the mechanism of action was broadly suggested as an improvement in penile haemodynamics.8 Although this finding is very promising it certainly needs to be validated in larger studies. The current clinical guidelines do not recommend the routine use of LI-ESWT in the treatment of ED.9
Long-term daily use of PDE5-Is
In recent years another indication for PDE5-Is has emerged as daily administration in patients with postoperative ED starting from early postoperative period instead of the on-demand use as indicated on the product label. This application is based on a landmark study, which showed the prevention of the onset of penile tissue damage by regular pharmacological (for example, alprostadil injection) stimulation of penile erection to improve oxygenation of corpora cavernosa.10
Postsurgical penile rehabilitation programmes using PDE5-Is as pharmacologic stimulants of erection have been recently investigated and it is proposed that the increased anti-apoptotic and anti-fibrotic activities in corpus cavernousum are caused by elevation of NO and cGMP levels associated with the use of PDE5-Is.
A very recent randomised controlled trial (RCT) showed better erectile functions in patients receiving daily tadalafil11 while other previous RCTs showed no significant difference in daily usage compared to on-demand administration.12
Data from multiple animal studies support the concept of using PDE5-Is in postoperative penile rehabilitation and human trials also support that stimulating penile erections either pharmacologically or with vacuum erection devices are associated with better erectile functions. However, definitive data to support the routine use of PDE5-Is in postoperative penile rehabilitation is currently not available.
Several treatment options are currently available including PDE5-Is, intracavernousal injections and penile prosthesis implantation that are graded as first-, second- and third-line treatment options in the European Association of Urology guidelines, respectively. Novel therapeutic strategies focus on curative treatment options like stem cell therapies, low-intensity extracorporeal shock wave therapy and long-term daily use of PDE5-Is.
Naside Mangir is currently a scholar of the European Association of Urology
- NIH Consensus Conference. Impotence. NIH Consensus Development Panel on Impotence. JAMA 1993;270(1):83–90.
- Lin G et al. Potential of adipose-derived stem cells for treatment of erectile dysfunction. J Sex Med 2009;6(Suppl 3):320–7.
- Ankrum J, Karp JM. Mesenchymal stem cell therapy: Two steps forward, one step back. Trends Mol Med 2010;16(5):203–9.
- Prockop DJ, Oh JY. Medical therapies with adult stem/progenitor cells (MSCs): a backward journey from dramatic results in vivo to the cellular and molecular explanations. J Cell Biochem 2012;113(5):1460–9.
- Yiou R et al. Safety of Intracavernous Bone Marrow-Mononuclear Cells for Postradical Prostatectomy Erectile Dysfunction: An Open Dose-Escalation Pilot Study. Eur Urol 2015.
- Haahr MK et al. Safety and Potential Effect of a Single Intracavernous Injection of Autologous Adipose-Derived Regenerative Cells in Patients with Erectile Dysfunction Following Radical Prostatectomy: An Open-Label Phase I Clinical Trial. EBioMedicine 2016. In press.
- Albersen M, Lin C-S, Lue T. Stem-cell therapy for erectile dysfunction. Arab J Urol 2014;11(3):237–44.
- Vardi Y et al. Does Low Intensity Extracorporeal Shock Wave Therapy have a physiological effect on erectile function? Short-term results of a randomized, double-blind, sham controlled study. J Urol 187(5):1769–75.
- Hatzimouratidis K et al. Guidelines on male sexual dysfunction: Erectile dysfunction and premature eaculation. Eur Urol 2010;57(5):804–14.
- Montorsi F et al. Recovery of spontaneous erectile function after nerve-sparing radical retropubic prostatectomy with and without early intracavernous injections of alprostadil: results of a prospective, randomized trial. J Urol 1997;158(4):1408–10.
- Montorsi F et al. Effects of tadalafil treatment on erectile function recovery following bilateral nerve-sparing radical prostatectomy: a randomised placebo-controlled study (REACTT). Eur Urol 2014;65(3)587–96.
- Montorsi F et al. Effect of nightly versus on-demand vardenafil on recovery of erectile function in men following bilateral nerve-sparing radical prostatectomy. Eur Urol 2008;54(4):924–31.