Erectile dysfunction is a common concern among aging males. Not only does ED affect quality of life, but it is also linked to cardiovascular disease, hypertension, diabetes, and overall health.
Currently, there are three categories of ED treatments. Oral medications such as phosphodiesterase type-5 (PDE-5) inhibitors (sildenafil, vardenafil, tadalafil, and avanafil) have comparable efficacy. Intracavernosal injections (alprostadil, phentolamine, papaverine, and/or atropine) or intraurethral suppositories (alprostadil) are alternatives in patients who are non-responders to oral medications or have side effects. Penile implants are the most invasive treatment but provide durable results and the highest satisfaction rates of all of treatments.
Given the prevalence of ED, there is significant incentive to find more effective and less invasive treatment options. Here we review new and emerging treatment options for this common condition. We also review the use of nutraceuticals, which are not new but have seen explosive growth in recent years (see, “Nutraceuticals for ED at a glance.")
New oral agents and pathways
PDE-5 inhibitors remain the cornerstone of oral therapies. Researchers have explored alternative pathways for novel therapeutics (table), although success has been limited. Currently, no novel oral medications are in clinical development. Prior targets have focused on central pathways (dopaminergic and melanocortin) and peripheral pathways (guanylyl cyclase and Rho-A/Rho kinase), but novel oral therapies directed at these pathways have shown limited efficacy and tolerability. An overview of the cellular pathways is shown in the figure.
Dopaminergic agents. Initially, the use of dopamine agonists for Parkinson’s disease was associated with increased libido. Apomorphine is a dopamine D1 and D2 receptor agonist that was approved for ED in Europe in 2001. In a phase III double-blind, parallel-arm, crossover study of nearly 900 men with ED, more than 50% of those using apomorphine were able to obtain an erection sufficient for intercourse compared to 33% of men using placebo (BJU Int 2002; 89:409-15). However, the FDA did not approve the drug in the United States because of concerns about hypotension. Similar medications (ABT-724 and ABT-670) targeted to the D4 receptor have also been studied, but development was stopped after phase II studies.
Melanocortin receptor agonists. Melanocortin receptor agonists including melanotan II (subcutaneous administration) and bremelanotide (intranasal administration) have been studied for ED. Both formulations improved erectile function in studied men, although they were poorly tolerated in clinical studies. Patients given melanotan II experienced severe emesis, and bremelanotide caused severe hypertension. Further clinical development has been discontinued.
Recently, a landmark study identified a single locus near the SIM1 gene that was associated with risk of ED independent of known risk factors in a large cohort (Proc Natl Acad Sci USA 2018; 115:11018-23). SIM1 encodes transcription factors involved in the leptin-melanocortin pathway and may represent an exciting target for future novel therapies.
Guanylyl cyclase activators. Soluble guanylyl cyclase is a key component of the nitric oxide (NO) pathway (figure). In post-prostatectomy patients or diabetics who have severe endothelial dysfunction and cavernous nerve injury, PDE-5 inhibition does not increase endogenous NO levels sufficiently. In these patients, direct activation of soluble guanylyl cyclase may enhance erections.
In a study of human cavernosal tissue obtained from patients during penile prosthesis implantation, compared to patients undergoing transurethral surgery, a combination of vardenafil and guanylyl cyclase activator enhanced cavernosal smooth muscle relaxation (J Sex Med 2013; 10:1268-77). Unfortunately, this medication has not progressed past phase II studies.
Rho kinase pathway. The RhoA/Rho kinase pathway contributes to cavernosal smooth muscle contraction, which is independent of the NO pathway. When activated, the smooth muscle myosin light chain (MLC) is phosphorylated by inhibiting MLC phosphatase, leading to calcium sensitization and smooth muscle contraction. Studies of hypertensive and diabetic rats have suggested upregulation of this pathway and a resultant worsening of erectile function. SAR407899 is a specific RhoA/Rho kinase inhibitor that induces penile erection with greater potency and longer duration than sildenafil in a diabetic rabbit model, as well as in human cavernosal tissue strips (J Transl Med 2012; 10:59). However, development of this drug ceased after completion of phase II clinical trials, without reporting of results.
Next: Topical agents