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Erectile Dysfunction
Advances in the Treatment of Erectile Dysfunction
a report by
Arthur L Burnett, MD
Professor, Department of Urology, Johns Hopkins University School of Medicine
Progress in the clinical management of erectile disorders,
and specifically erectile dysfunction (ED), has gained
substantially from basic science advances in the field.
Unquestionably, the advance of phosphodiesterase 5
(PDE5) inhibitor therapy quickly followed the basic
scientific description of nitric oxide (NO) signaling in
erectile tissue. Further investigation of the
neurotransmission involved in penile erection, hormone
actions involved in this response, and biochemical signal
transduction processes within the erectile tissue represent
major areas of scientific pursuit. Current objectives
scientifically are to identify and characterize molecular
targets operating at multiple levels of the nervous system,
endocrine system, and vascular system all related to penile
erection. It is conceivable that new knowledge involving
these systems may be exploited to develop various
therapeutic approaches to manage ED. These approaches
include pharmacotherapy, growth factor interventions, cell
and tissue engineering, and gene therapy.
C e n t r a l N e r vo u s S y s t e m Ta r g e t s
At the level of the central nervous system (CNS),
neurotransmitters and their receptors and neuronal
pathways represent molecular targets that may be
exploited for the purpose of treating ED. Prominent
among these are the chemicals dopamine,
melanocortin, oxytocin, hexarelin analogue, serotonin,
noradrenaline, and NO. The dopaminergic system has
already been approached at the clinical level with the
development and use of apomorphine, a dopamine
receptor agonist. Regulatory approval for the human
use of this medication has been achieved in countries
outside of the US. However, because of nausea and
syncope, the medication has not been approved for
clinical distribution in the US. Nonetheless, preclinical
studies have continued to show that the dopaminergic
system may be fruitful for clinical applications, and
further studies of this sort may lead to the development
of dopamine-selective agonists operating at specific
receptor subtypes in the human brain that exert optimal
clinical efficacy without adverse effects.
An additional system that has gained great interest for its
potential in the treatment of ED is the melanocortinergic
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system. Early phase clinical trials have demonstrated that
PT-141, a cyclic heptapeptide melanocortin analogue,
elicits erectile responses in both healthy men and men
with mild-to-moderate ED. These trials have
demonstrated responses in men who were non-responsive
to PDE5 inhibitor therapy. The medication can be
administered by either intranasal or subcutaneous routes.
Study participants have tolerated the medication only
reporting occasional flushing and nausea. At this time,
regulatory agency approval of this medication has not yet
been achieved. Further studies are necessary to develop
and evaluate drugs contended to have utility via other
select neuronal systems at the CNS level.
Pe r i p h e r a l Ta r g e t s
Chemical released at terminations of the peripheral
nervous system in the penis and by cellular constituents of
this tissue, which have shown physiologic effects on the
relaxant response of this tissue, point to possible peripheral
targets that could be exploited clinically. These targets
include not just the chemical mediators themselves but
also the molecular signal transduction systems through
which they operate. Current knowledge has led to the
definition of various chemical mediators and their
mechanisms whereby pharmacotherapeutic regimens
have been based. For instance, α-adrenoceptor antagonists
such as phentolamine, the prostanoid prostaglandin E1,
and the non-specific phosphodiesterase papaverine have
been
prominently
used
for
intracavernosal
pharmacotherapy. Additional interest has turned to
alternative approaches to oppose cavernosal tissue
vasoconstriction, which if controlled could promote the
erectile response. Thus, agents such as endothelin
antagonists, vasoconstrictive prostanoid inhibitors, and
inhibitors of the RhoA/Rho-kinase pathway could
represent exciting new directions for clinical
management.The RhoA/Rho-kinase pathway has been
shown to be a major site of convergence for many
vasoconstrictive mediators, such that targeted therapy
exploiting this pathway may afford a tremendous
approach to promote erectogenesis. It is recognized that
the ubiquitous characteristic of this pathway in the body
presents a challenge for assigning its utility for genital
responses. Specific drugs that target penile tissue, perhaps
Arthur L Burnett, MD, is Professor
in the Department of Urology at
Johns Hopkins University School of
Medicine in Baltimore, Maryland,
where he is also Director of the
Basic Science Laboratory in
Neurourology. Currently, Dr Burnett
holds professional appointments at
the Johns Hopkins Hospital,
including Director of the Male
Consultation Clinic and
researcher/clinician at the James
Buchanan Brady Urological Institute.
He is an active staff member at
both the Johns Hopkins Hospital
and the Johns Hopkins Bayview
Medical Center. Dr Burnett received
his undergraduate degree in biology
from Princeton University and
subsequently his medical degree at
Johns Hopkins University School of
Medicine. He then completed his
internship and residency in surgery,
and subsequently residency and
fellowship in urology at the Johns
Hopkins Hospital. Upon completion
of his urology residency, he also
received an American Foundation of
Urologic Disease New Investigator
Award to continue research work
into the regulatory basis of nitric
oxide in the mediation of penile
erection. He has maintained an
active laboratory in neuro-urology
since that time.
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Erectile Dysfunction
by specific Rho-associated proteins, would seem to be a
potential direction to induce intended effects without
causing adverse effects elsewhere.
The knowledge that the NO signaling mechanism is the
main player in controlling the erectile response in the
penis has led to initiatives to investigate and target
components of this pathway more fully for the treatment
of ED. Already, PDE5 inhibitors operate by this pathway,
and clinical efficacy of this class of medications, which
includes sildenafil, vardenafil, and tadalafil, has been well
established. Guanylate cyclase activation has also rapidly
emerged as a possibly important mechanism associated
with the NO pathway that could have clinical relevance.
Preclinical studies applying guanylate cyclase activators
have been performed in vivo showing erectogenic
potential. For the future, this pathway may be further
studied with the identification of specific molecular sites
applicable for ED management.
Growth Factor Therapy
Growth factor interventions for ED management refer to
therapies based on chemical factors relevant for the
structural and functional health of the penis.
Neurotrophins such as nerve growth factor fill a category
of therapies known as therapeutic neurogenesis and have
applications for neurogenic ED. Angiogenic factors such
as vascular endothelial growth factor may facilitate
signaling and homeostasis of the vascular system relevant
to the erection response. Such categories represent
neuroprotection and vasculoprotection, respectively, and
bring high levels of excitement because of their
conceivable corrective influence in the face of disease
states causing ED. At this time, further clinical studies
are warranted to establish the exact potential for growth
factor therapy in the management of ED.The key issues
are whether such molecular sites can be targeted in such
a way for controlled therapeutic purposes without
causing untoward proliferative or dysfunctional effects
involving structures elsewhere in the body.
Cell and Tissue Engineering
Cell and tissue reconstitutive therapies also draw
substantial interest because of their potential to correct
ED and restore normal erectile function. Nerve
reconstruction, the structural repair or reconnection of
nerves after injury of the autonomic nerve supply to the
penis, has already been introduced to the field clinically
with the application of autologous cavernous nerve
interposition grafting at the time of radical prostatectomy.
The concept for this purpose is particularly intriguing,
but confirmed success with nerve grafting presently
remains limited. On-going investigation in this field may
lead to alternative grafting materials and techniques
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having greater success in the future.
The basic scientific area relating to tissue reconstruction
for the penis is in its infancy, although much promise for
this approach in the future is anticipated. Preclinical work
has demonstrated the feasibility of tissue engineering
approaches.This work encompasses the creation of genital
structures with the admixture of smooth muscle,
endothelial cells, and other components of erectile tissue
including nerves and connective tissue. Because of the
architectural, biomechanical, and functional requirements
of the penis and its associated structures, progress in this
field will be a major challenge.
Gene Therapy
Gene therapy does represent a potentially exciting new
direction for ED management.The concept is based on
the introduction of foreign genetic material into human
cells either to restore or supplement normal cellular
function. The exact role would be to correct defective
function or otherwise functionally antagonize the effects
of an adverse genetic phenotype. Numerous preclinical
studies have been carried out in the field of ED
demonstrating the high feasibility of such intervention.
The penis offers several unique and suitable properties
for gene therapy, including its external accessibility, its
content of smooth muscle cells of which only a small
fraction may need to be modified for functional
purposes, and the low turnover rate of these cells which
evidently permit longstanding gene expression.
Presently, the intracavernosal administration of hSlo
cDNA, which encodes for the large-conductance
calcium-sensitive maxi-K channel, has moved forward in
early human clinical testing, suggesting that it has
promise clinically. It is acknowledged that major safety
hurdles as well as requirements for controlling a
conditional response will need to be met before
implementing this therapy in the future.
Summary
Significant advances have been made in the past 20 years
in the science and medicine of ED. A host of treatments
are either newly available qr emerging for this purpose.
Advances have clearly been based on an increased
knowledge of the basic mechanisms of penile erection
and that associated with its pathophysiology. It is
recognized that ideal interventions for ED should fully
restore natural erectile ability. This notion then implies
that an intervention would be applied with long-term
efficacy and in the absence of repeated administrations.
This field is clearly unlimited when one considers
multiple possibilities for medical advance ranging from
pharmacotherapeutics to gene therapy. Undoubtedly, the
future of ED management is eagerly awaited. ■
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