The Future of Erectile Dysfunction Therapy II: Novel Pharmacotherapy and Innovative Technology

Abstract

While current treatment modalities for erectile dysfunction have become easier to administer and more scientifically based and clinically accepted, they still have their shortcomings such as inconvenience, limited efficacy, and spontaneity. These shortcomings are well recognized in the field, with many investigators exploring improved methods to meet this objective. Broadly speaking, such directions include novel pharmacotherapy, innovative technology, tissue engineering, and creative mechanical approaches. Here we provide an overview of the future of erectile dysfunction treatments.

Appendices

Commentary: The Future of Erectile Dysfunction Therapy II—Novel Pharmacotherapy and Innovative Technology

• Michael A. Perelman Ph.D. &
• Alexander W. Pastuszak M.D., Ph.D. 

1. Reproductive Medicine and Urology, Weill Medical College Cornell University, New York, NY, USA

   Michael A. Perelman Ph.D. (Psychiatry, Co-Director, Founder)

2. Human Sexuality Program, The New York Presbyterian Hospital, New York, NY, USA

   Michael A. Perelman Ph.D. (Psychiatry, Co-Director, Founder)

3. MAP Education and Research Fund, New York, NY, USA

   Michael A. Perelman Ph.D. (Psychiatry, Co-Director, Founder)

4. Division of Male Reproductive, Medicine and Surgery, Center for Reproductive Medicine, Scott Department of Urology, Baylor College of Medicine, Houston, TX, USA

   Alexander W. Pastuszak M.D., Ph.D.

Men with erectile dysfunction (ED) commonly visit their physician first when seeking treatment and are often prescribed medical first-line therapy for their ED. However, these therapies are incompletely effective, and there is a growing understanding that ED, even when organic in origin, has a psychosocial component. This psychosocial contribution is often overlooked or not known by treating physicians. As a result, treatment escalation in most men with ED often remains focused on medical, and finally surgical, therapies, at which point psychotherapy is moot. It is imperative that clinicians understand that ED has psychological ramifications and do not lose sight of the positive effects of incorporating psychotherapy into the treatment of these men. Such a combined therapeutic approach may improve the response to both medical and psychotherapies and decrease the need or dosage of medical therapies.

While Burnett and Kovac focus on the future of ED therapy from a medical perspective in their chapters, a truly comprehensive understanding of the future of ED therapy incorporates an understanding of psychotherapeutic approaches as well. As such, the following commentary highlights psychosocial cultural factors and corresponding mental health approaches to ED that, when applied in combination or in lieu of medical therapies, will optimize ED therapy. A combined, collaborative approach to ED therapy, irrespective of the medical therapy, truly represents the future of ED therapy.

The Editors

Commentary

Brian V. Le and Arthur L. Burnett’s chapter provides an excellent overview of future opportunities for erectile dysfunction (ED) treatment from a biological point of view with its emphasis on the probable emergence of novel pharmacotherapies, growth factor and stem cell therapies, and mechanical technologies. Le and Burnett also touch on the potential for some of those therapies to be combined with both each other and existing medical treatments to enhance efficacy beyond what is currently available today. However, an appreciation for the additional improvements that a psychosocial-behavioral and cultural (PSBC) paradigm would provide has eluded mention in their chapter and others in this text. Such an integration is not only key to optimizing efficacy; it can also improve treatment safety as drug dosage can be reduced with the inclusion of non-pharmaceutical factors that enhance response to ED treatment. The benefits and rationale for using an integrated treatment approach were partially elucidated in chapter one and have been described extensively elsewhere [1, 2]. An integrated approach can be easily understood using a number of dual control paradigms. However, the Sexual Tipping Point (STP^®) model is especially useful when it comes to illustrating integration of future medical modalities within a biopsychosocial-behavioral and cultural model (see Fig. 1.2, 1.3, 1.4). In short, the STP^® model provides a conceptual framework for an optimized, integrated treatment approach for every novel future therapy summarized by Le and Burnett.

All cases of ED can be considered of “mixed” etiology, with contributions from both organic and PSBC components [3, 4]. Sachs suggests that there are “neural, neurochemical, and endocrine mechanisms whose participation in erectile function depends on the behavioral context in which erection occurs” [5]. Thus, optimal therapy for ED, and for any sexual dysfunction for that matter, should be approached with an understanding that both the physical and mental aspects of the sexual dysfunction are essential contributors to the pathology and that addressing both facets of the condition will offer the most significant improvements [6]. To provide an example using existing treatments, discontinuation rates of phosphodiesterase 5 inhibitor (PDE5i) therapies in men with ED approach 50 % [7], but 18 % of men who discontinue PDE5is have psychological factors that can readily be addressed using combination therapy [8–12]. Other psychosocial factors, including a couple’s dynamics, a man’s approach to sex with his partner, and the couple’s expectations of the effects of the medical intervention in their love life, are often less obvious to the physician, but are nevertheless essential in restoring full sexual function and are often not considered [13]. By extrapolating from studies of men undergoing psychotherapy where erectile function improvements were observed in the absence of medication [14, 15], as well as examining response rates of ED to placebo in randomized clinical trials (RCTs), it is reasonable to predict that all of the novel treatments Le and Burnett describe could be “dose” titrated down to improve safety profiles when attention to PSBC variables is integrated into the treatment approach. Support for such integration may be found by examining early reports of adjunctive sex therapy for men suffering from organic ED who underwent penile prosthesis placement. Counseling helped set expectations and facilitated the integration of the prosthesis into the sex life of the couple and often resulted in increased patient and partner satisfaction [16–21]. Much recent work argues for an integrative treatment approach in men with ED, and steady progress towards this goal is being made [9, 11, 22–25].

A transdisciplinary approach, whether offered by a solo practitioner or a multidisciplinary team, should always be considered, even as other improvements in systems medicine stand to revolutionize treatment of ED and other sexual dysfunctions [2]. A primary care practitioner (PCP) or urologist may integrate sex counseling with the use of pharmacotherapy in their treatment of ED within the limits of their skill set and available time. The most important PSBC factors can frequently be identified during the course of a proper diagnostic interview using standard techniques for obtaining a focused sexual history and current sex status [26]. However, a collaborative approach, whether using a virtual or in-house team involving sex therapists and the patient’s medical care team, will further facilitate and improve care of these patients, particularly in cases with moderate or severe psychosocial complexity where the principle etiologic factors of the patient’s ED lie outside the primary provider’s expertise [18, 27]. There is even evidence, which only future research will confirm, that such behavioral and cognitive interventions change brain chemistry and neuropathways in a manner that makes success more continuous and minimizes risk of relapse.

Like all medical interventions, future therapy for ED must consider and should rely on a patient-centered approach, guiding treatment based on a patient’s goals [12, 18, 28]. Involvement of the patient’s partner in the assessment and treatment process is almost always preferable [29]. Yet, urologists who frequently see the man for treatment alone may find it comforting that sex therapy research supports partner cooperation, rather than attendance at each office visit, as the key to treatment success [21]. Nonetheless, regardless of the development and deployment of novel effective and safe approaches to ED, all clinicians are well reminded to emphasize patient and partner pleasure and satisfaction over objective performance, as exemplified by the “Good Enough Sex” model by Metz and McCarthy [30]. Again, the use of a “sex status” examination, which focuses on identifying all the key factors relating to the patient’s ED, is critical in comprehensively understanding the landscape of the patient’s problem and can help to identify appropriate medical and psychosocial interventions, highlighting the utility of an integrative approach [24]. Of course, the need for patient education and regular follow-up cannot be emphasized enough regardless of treatment novelty, as these facilitate adherence to treatment [11, 31, 32].

In much the same way that Le and Burnett describe exciting targets for both selective inhibition and stimulation of binding proteins that would facilitate erectile activity without adverse consequences elsewhere in the body, psychosocial-behavioral interventions derived from traditional sex therapy, cognitive behavior therapy, and systems approaches all help optimize the efficacy of these future pharmaceutical interventions [1]. Several key signaling pathways and molecules, including nitric oxide (NO) synthases and endogenous NO levels, the angiotensin receptor, extracellular signal-related kinase (ERK), guanylate cyclase modulators, and Rho/RhoA kinase, are highlighted by Le and Burnett as novel pharmacotherapeutic targets. While these pathways and molecules are critically important in the physiologic ability to initiate and maintain an erectile response via positive and negative influences on their respective pathways, and thus the STP^®, one must also consider the psychological processes acting through a cascade of central effects, which further influence the STP^®. Like PDE5is, sexual stimulation (both mental and physical) will likely potentiate the action of pharmacotherapies targeting the above pathways [15], further highlighting the mind-body connection in sex.

As one contemplates an integrative model, enhancement of arousing factors and minimizing of inhibiting factors must be considered. When discussing growth factors, Le and Burnett focus on neurotrophic and angiogenic factors that are now known to play major roles in penile function and may be of particular interest in situations where damage to the cavernosal nerves occurs, such as post-prostatectomy. Similar to the considerations with pharmacotherapies, each growth factor functions by stimulating a specific physiologic pathway, resulting in improved penile function and exerting a positive influence, tipping the STP^® balance scale towards greater sexual responsiveness. While penile physiology may improve using medical treatment, the psychological grief and adjustment that is often an integral part of post-prostatectomy ED [33] is clearly an inhibitor, which is often best addressed using counseling alone or in combination with pharmacotherapy [34].

Although stem cell therapies are oriented towards replacing nonfunctional tissue to restore the natural processes that facilitate erection rather than modulating existing pathways, their impact on physiology likewise integrates excitatory and inhibitory functions and fits into the STP^® model, much like the effects of the other medical therapies described by Le and Burnett. Similarly, pudendal artery stenting, low-intensity extracorporeal shock wave therapy (LI-ESWT), and penile vibratory stimulation also improve penile physiology and help to maximize physical potential, but in the absence of optimized psychosocial-behavioral and cultural factors, the patient’s STP^® may remain closer to “Not” than “Hot,” and his true potential remains unmet.

Finally, experimental design is an additional relevant factor that should be considered when evaluating all the exciting potential new treatments for ED described by Le and Burnett. Specifically, advances in understanding the placebo effect and its application to sexual disorders are important considerations [35, 36]. One of the most important elements that psychology brings to medical and pharmaceutical evaluation is the notion of placebo, placebo response, and placebo effect. We should remain mindful that these variables impact our studies and that careful scientific evaluation requires an understanding of these concepts. It is well known that responses to placebo often well exceed 20 % in RCTs evaluating ED treatments. Evidence has also surfaced in some psychiatric drug trials that the therapeutic setting and frequency of visits can account for over 50 % of observed positive responses. To what extent is this true for clinical trials in sexual medicine? It makes intuitive sense that more frequent contact and follow-up with patients may contribute to better responses, and this is supported by the relapse prevention literature [37]. In fact, this effect is even more pronounced in older adults, the very demographic more likely to be suffering from ED [36]. It would be extraordinary if we could better understand how to minimize the placebo effect, particularly in clinical trials, and maximize it during treatment! That indeed would be the type of elegant advance resulting from integration of knowledge from two seemingly disparate areas of science. Yet the benefit to researchers, clinicians, and patients alike would be both remarkable and profound.

In conclusion, it is our belief that almost every sexual experience, whether or not facilitated by a pharmaceutical (or alternative technology), could be enhanced by an increase in erotic thought, a reduction in distracting negative intrusive cognitions, and better quality and pleasing “friction.” Improving these elements or more simply put increasing “friction and fantasy” has been advocated by sex therapists for decades [11]. Reciprocally, identifying and successfully targeting key signaling pathways and molecules in the manner outlined by Le and Burnett will improve the erectile capacity of men well beyond the early successes of the last 20 years. The STP^® model provides a framework for understanding the subtleties of the combined and variable effects of physiology and psychobiology in sexual function. Such an understanding that addresses all factors involved in the dysfunction will truly optimize, and in the future revolutionize, treatment of ED and other sexual dysfunctions. Integrating medical therapy and counseling potentiates the individual approaches, and the sum of the parts is significantly greater than each part alone (see Fig. 1.4).

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