Over 250 years have elapsed since induratio penis plastica
was first described by Francois Gigot de la Peyronie, surgeon to Louis XV. This
benign condition of the penis has been the subject of voluminous literature but
little in the way of reliable medical therapies. Although the symptoms and signs
are uncomplicated, a balanced and cautious approach to the management of these
patients is required to achieve optimum long term satisfaction.
Peyronie's disease is estimated to affect between 1 and 3% of the male
population with a peak incidence occurring in the fifth decade. A
questionnaire-based study of over 4000 respondents found that 3.2% of the
respondents between the ages of 30 and 80 years reported palpable plaques in the
penis. The classic presenting symptoms are curvature of the erect penis, penile
pain, erectile dysfunction and the presence of a palpable plaque arising from
the tunica albuginea. The plaques may progress to become nodular with very
severe cases showing signs of calcification and ossification. Complete
spontaneous resolution can occur in 13-40% of patients. The disease has also
been reported to occur in association with other conditions (Dupuytren's
contracture, Ledeshore's disease, Tympanosclerosis, Paget's disease, and
Diabetes) indicating a likely genetic predisposition or a possible underlying
autoimmune basis for disease initiation and progression. Globally, the incidence
of this condition appears to be increasing. This may be indicative of the wider
availability and use of oral pharmacotherapies in impotent men, which allows
identification of those patients who would otherwise have been unaware that they
had a penile curvature. This also reflects the greater awareness of male sexual
dysfunction within our society due to broad media coverage and the acceptance
that conditions such as Peyronie's disease can be openly discussed and brought
to the attention of primary care practitioners without embarrassment.
The normal tunica albuginea of the penis is composed of a
lattice of collagen and elastic fibres which are arranged in two layers: an
outer longitudinal laver responsible for elongation of the penis during erection
and an inner circular layer responsible for increasing the width. Emissary veins
and arterial branches traverse the layers of the tunica and allow communication
between the erectile tissue and the dorsal vasculature of the penis. During the
early phases of the disease, cellular infiltrates consisting of T lymphocytes,
macrophages and plasma cells surround the small vessels in the subtunical layer.
This inflammatory infiltrate is later followed by focal areas of fibrosis that
eventually develop into mature plaques.
Histological examination of excised plaques shows that fibrin deposition occurs
within the plaques together with dense collagenous connective tissue and
calcification. Areas of fibrosis may then extend into the erectile tissue as
well as transgressing the tunical layer.
There are several theories which have been proposed to explain the disease process occurring in Peyronie's disease. The most widely accepted theory is that the disease process is initiated by tunical mechanical stress and microvascular trauma to the erect penis which results in aberrant wound healing and subsequent scar tissue formation. Alternative theories suggest that plaque formation is a manifestation of an autoimmune disease initiated by an infectious agent. A genetic predisposition may also have a role since Peyronie's disease is associated with other fibrotic conditions such as Dupuytren's contracture (10-20% incidence in Peyronie's disease) and Ledeshore's disease as well as human lymphocyte antigen (FILA)-B7 antigens.
Peyronie's disease presents in two distinct phases, an
inflammatory phase lasting approximately 3-12 months where patients develop
progressive penile curvature and penile pain followed by a chronic phase
characterized by stable plaque formation and a variable degree of erectile
dysfunction.
Mechanical stress and microvascular trauma
The imbalance between profibrotic and antifibrotic factors plays a key role in
the ultimate development of a tunical plaque. As mentioned already, the
initiating factor appears to be microvascular trauma occurring during sexual
intercourse. This leads to subtunical bleeding and delamination of the tunica
albuginea with subsequent fluid and fibrinogen leakage into the subtunical
layers. Extravascular leakage of blood results in the release of
platelet-derived growth factors such as MGF-A and MGF-B and also transforming
growth factor (TGF)-B1.
Immunohistochemical studies have shown strong expression of MGF-A and PDGF-B in
fibroblast-like cells in the tunica albuginea obtained from patients with
Peyronie's disease. Thrombogenesis and deposition of fibrin leads to the
initiation of the wound healing response with macrophage, neutrophil and mast
cell recruitment. Neutrophils are the predominant inflammatory cell type in the
first 24 hours and macrophage recruitment occurs at 48 hours. The release of
cytokines and vasoactive factors initiates the fibrogenesis. The subsequent
migration and proliferation of fibroblasts in response to growth factors
released by platelets and macrophages is followed by fibroblast differentiation
into myofibroblasts. In normal wound healing the paracrine effects of growth
factors assist in wound closure following which the myofibroblasts undergo
apoptosis. It is postulated that in certain conditions, e.g. Dupuytren's
disease, these myofibroblasts persist resulting in abnormal fibrosis. It is
plausible that a similar mechanism occurs in plaque development during
Peyronie's disease.
Plaque development and TGF-ß1
TGF-ß1 appears to increase the synthesis of collagen, proteoglycans and
fibronectin in addition to the tissue inhibitors of collagenase, the overall
result being that fibrogenesis is potentiated. TGF-ß1 is synthesized by various
cell types including platelets, fibroblasts and macrophages as an inactive,
latent peptide. Once activated, TGF-ß1 binds to specific cell surface receptors
and not only activates a signal cascade leading to the synthesis of connective
tissue but also simultaneously inhibits collagenases. Evidence for the role of
TGF-ß1 in the pathogenesis of Peyronie's disease has been gathered from both
human and animal studies. Increased expression of TGF-ß1, TGF-ß2 and TGF-ß3 has
been found in patients with Peyronie's disease when compared with non-Peyronie's
patients using plaque and tunica albuginea biopsies. Further evidence for the
role of TGF-ß1 appears from a rat model of Peyronie's disease utilizing subtunical injections of the synthetic heptapeptide cytomodulin which stimulates
TGF-ß1 expression. After 6 weeks of cytomodulin injection, tunical thickening
and plaque formation occurred. In addition to this TGF-ß1 mRNA expression was
found to have increased.
TGF-ß1 also transcriptionally represses inducible nitric oxide synthase (iNOS)
production therefore overall nitric oxide (NO) production is reduced. The
antifibrotic effects of NO will be discussed later.
Reactive oxygen species
Reactive oxygen species (ROS) are highly reactive oxidizing agents and include
superoxide anion (O2), hydrogen peroxide (H202), and the nitrogen-derived free
radicals NO and peroxynitrite anion (ONOO-). The localized inflammatory reaction
following penile trauma may result in excessive ROS generation. The presence of
ROS can activate a range of cellular mediators implicated in the inflammatory
phase of the disease process. Cell membrane lipid peroxidation due to the
presence of free radicals results in an increase in vascular permeability. This
is followed by leakage of fibrogenic factors and subsequent activation of
fibroblasts, neutrophils and macrophages. This forms the basis for the use of
free radical scavengers and antioxidants as a therapeutic option in Peyronie's
disease. NO has an antioxidant effect on ROS leading to the production of
peroxynitrite. Additionally, elimination of ROS by antioxidant enzymes such as
superoxide dismutase, catalase and xanthine oxidase can also occur. Therefore it
appears that an overall imbalance between ROS and NO can result in fibrogenesis.
The complex antifibrotic effects of NO are not exclusively through reducing the
levels of ROS but may also involve modulating the fibrogenic activity of
endothelin and angiotensin. It may also stimulate the activity and expression of
metalloproteinases.
There are two distinct phases in the natural history of Peyronie's disease.
The initial inflammatory phase, characterized by progressive penile curvature and pain, can last
for 12 months followed by a stable painless phase. It is
important to avoid surgical intervention during the inflammatory phase. The
evaluation of a patient presenting with Peyronie's disease should include a
thorough medical and sexual history. This will help to differentiate between
the early and late phases of the disease and whether any medical or surgical
intervention is indicated.
Examination
Classically, a Peyronie's plaque is found in the dorsal midline of the
penile shaft. Lateral and ventral plaques are less common, however, if they
are present there is a significant deviation of the natural angle of coitus
thus making sexual intercourse particularly problematic. More complex plaques
can be circumferential resulting in an hourglass deformity of the penis with
distal penile flaccidity. Gentle stretching of the penis helps in identifying
the site and size of the plaques which should be recorded diagrammatically to
assist in the monitoring of plaque progression. The stretched penile length is
measured from the urethral meatus to the level of the abdominal skin. Penile
shortening usually occurs even before surgical intervention. In order to
monitor disease progression, the angle of deformity is documented using either
an intracavernosal injection of a vasoactive agent or digital photography. The
use of vasoactive intracavernosal injections is also useful in patients who
have concomitant erectile dysfunction.
Erectile dysfunction associated with Peyronie's disease
may be due to a combination of factors.
Psychogenic: the presence of an obvious penile deformity can precipitate
anxiety-related erectile dysfunction. This feature is more common in early
relationships as opposed to longstanding relationships.
Hourglass deformity: circumferential plaques can prevent adequate tumescence of
the distal segment of the penis. This lack of rigidity can result in problematic
penetration.
Vasculogenic: erectile dysfunction may be due to concomitant vascular disease
that occurs in 30% of patients with Peyronie's disease or site specific veno-occlusive
dysfunction. An emissary vein may pass through a Peyronie's plaque into the
dorsal vein of the penis and cannot be compressed between the tunical layers.
Patients may then present with a flaccid distal portion of the penis or a soft
glans penis, the proximal segment being normal. There is controversy as to the
mechanism of this, be it arterial, venous or fibrotic in nature but certainly a
significant symptom of advanced organic disease. Extensive investigations are
not always required in the early stages of the disease. The diagnosis can be
made with a thorough history and examination. However, in patients who are being
considered for surgery, imaging techniques can assist in delineating the plaques
and accurately assessing the preoperative erectile function.
Colour Doppler ultrasound and magnetic resonance imaging
Colour Doppler studies performed before and after the injection of vasoactive
agents allow more detailed assessment of the areas of involvement and plaque
dimensions. The arterial and venous flow can be assessed, particularly if
preoperative erectile dysfunction is also present or the true extent of the
dysfunction is still unclear. Severe vasculogenic erectile dysfunction which has
not been helped using phosphodiesterase inhibitors indicates that surgical
correction of the penile deformity will not necessarily improve potency
postoperatively. Therefore a penile implant is an appropriate alternative.
Contrast-enhanced magnetic resonance imaging (MRI) is reserved for patients with
complex and extensive cavernosal fibrosis. The fibrosis can often be seen
extending deep into the erectile tissue of the corpus cavernosum resulting in
significant hourglass deformities.
Oral treatment options
Since oxidative stress and activation of collagen synthesis have been widely
implicated in disease progression, pharmacotherapies have specifically targeted
these two pathways in the form of antioxidants and collagen synthesis
inhibitors. Generally, pharmacotherapies are found to be most efficacious in the
inflammatory phase of the disease process.
Vitamin E (alpha-tocopherol)
Vitamin E is an antioxidant which is used to prevent fibrosis with no reported
side effects. It interacts with ROS such as OH. and reduces the molecule to an
inert state. Although early studies reported a significant reduction in the
penile curvature and reduction in plaque size, larger cohorts have shown between
35 and 99% of patients report a decrease in pain with only 10-33% reporting an
improvement in penile angulation.
With debatable overall improvement in the degree of deformity, vitamin E still
has a limited role in the management of early Peyronie's disease.
Potaba (potassium para-aminobenzoate)
Oral Potaba increases monoamine oxidase, decreases serotonin, increases oxygen
utilization and therefore reduces overall free radical generation. Potaba
inhibits abnormal fibroblast proliferation, acid mucopolysaccharide and
glycosaminoglycan secretion and thus has a wide variety of uses in chronic
inflammatory disorders including pulmonary fibrosis and scleroderma.
However, the use of Potaba is fraught with limitations including the high dosage
regime (12 g per day), high cost and gastrointestinal side effects. Evidence for
the efficacy of Potaba is also limited with studies being of small size and
generally uncontrolled. A placebo controlled double-blind trial of 41 patients
showed no statistically significant benefit at all.
Colchicine
An alkaloid derivative from the autumn crocus, Colchicum autumnale, colchicine
binds to tubulin and interferes with microtubular structure and function.
Colchicine is likely to have several other mechanisms of action which include
inhibiting the release of inflammatory cytokines and inhibiting phospholipase A2
which also reduces eicosanoid production. In vitro studies have demonstrated
that colchicine inhibits the proliferation of fibroblasts cultured from
Peyronie's plaques. Colchicine -treated animals also demonstrate a reduction in
collagen deposition in the tunica albuginea. Clinical trials using ultrasound
techniques to measure plaque size and intracavernosal injections to measure
penile angulation have shown that there is 70-95% improvement in pain and 30-55%
improvement in the penile angulation. Overall efficacy is improved in patients
who have had the disease for a short period and who have a penile curvature of
less than 30 degrees.
Tamoxifen
This non-steroidal antioestrogen appears to modulate the inflammatory response
by reducing TGF-ß1 secretion from fibroblasts. As previously stated TGF-ß1 not
only stimulates the synthesis of connective tissue matrix, but also inhibits
matrix degrading proteases. As with colchicine, tamoxifen treatment is most
efficacious in patients with early disease but there are still conflicting data
regarding the efficacy in Peyronie's disease. An early clinical trial reported
an improvement in pain of 80% with improved angulation of 35% when tamoxifen was
taken at a dose of 20 mg twice daily for at least 3 months. However, a
randomized placebo controlled study found no significant improvement in pain or
angulation.
Intralesional injection treatment
Both verapamil and interferon-alpha have been instilled directly into the
Peyronie's plaque. Although there are limited data, there does appear to be a
degree of symptomatic improvement in these patients.
Verapamil
It has become evident that exocytosis of extracellular matrix molecules
including collagen and glycosaminoglycans is a calcium-mediated event. The use
of calcium antagonists results in a morphological change of the fibroblasts
resulting in an alteration in the secreted protein phenotype. Verapamil inhibits
collagen synthesis and is effective in plaque softening and dissolving when
injected intralesionally. Recent studies have shown that verapamil inhibits the
expression of collagen and increases the activity of collagenase. Expression of
cytokines including PDGF-BB, interleukin IL-6 and IL-8 which have an important
role in the early phases of the wound healing response is also altered.
However, clinical data is limited due to the lack of controlled studies. The
most recent studies utilizing verapamil have shown an improvement in pain
severity and penile angulation regardless of the duration and severity of the
angulation. Other studies have reported pain resolution in 97% of patients and
penile curvature was reduced by 54% when injections were used every 2 weeks for
12 weeks. In a more recent series, with a follow-up of up to 6 years, 60% of men
reported an objective decrease in the curvature with very few complications
being reported. Long term follow-up did not show further disease progression in
this group of patients.
Interferon-alpha-2b
Interferons (IFNs) are a group of low molecular weight proteins and
glycoproteins. The potential usage of interferons developed from in vitro work
using Peyronie's-derived human fibroblasts and the known effects of IFN-alpha2b
in decreasing keloid scars. Evidence for the use of intralesional IFN-alpha2b is
conflicting. However, studies which have found no significant effect from
utilizing IFN-alpha2b appear to have injected in the tissue adjacent to the
plaque as opposed to intralesionally. Support for the use of IFN-alpha2b has
been reported in relatively small studies. Intralesional injection of
IFN-alpha2b two to three times a week over a period of up to 6 months produced a
significant improvement in the penile curvature.
Extralesional therapy
Extracorporeal shock wave therapy
Although extracorporeal shock wave therapy (ESWT) has a well established role in
the management of renal calculi, in recent years a few studies have reported the
safety, tolerability and efficacy of ESWT in the treatment of Peyronie's
disease. In patients who have had unsuccessful oral therapy, ESWT has resulted
in a significant reduction in the penile curvature. ESWT has also been reported
to improve erectile function in patients with Peyronie's disease. In a recent
study, 28 patients underwent three to nine ESWT sessions. A total of 71 %
reported significantly improved erection and 49% were able to recommence sexual
intercourse. However, until ESWT has been evaluated in larger sample
populations, there still remains significant doubt as to whether this form of
treatment will become routine.
Radiotherapy
Low-dose radiotherapy has been utilized in the treatment of Peyronie's disease.
Patients irradiated with orthovoltage radiotherapy (200 and 250 kV photons) with
a total dose of 9 Gy have reported less pain (65%), reduced curvature (40%) and
an improvement in their sex life (50%). With a higher dose of radiotherapy 83%
reported that pain had diminished or disappeared and 23% reported a decrease in
penile curvature. It is recommended that radiotherapy be reserved as a
treatment option in cases of continuing pain after other treatment modalities
have been used. It may be particularly useful in the management of older
patients with multiple co-morbidities.
Surgical management of Peyronie's disease
Despite the diversity of medical treatments currently utilized for the early
management of Peyronie's disease, penile straightening operations are still
required in symptomatic patients with residual deformity. The aim of surgically
correcting the penile deformity associated with Peyronie's disease is to allow
penetrative sexual intercourse with minimal complications and shortening of
the
penis. Currently, the surgical procedures choice are: 1) Nesbit procedure 2)
plaque incision and grafting techniques 3) penile prosthesis. Patients with
dorsal deformities less than 45 degrees may be able to manage without surgery.
Younger patients, or those with ventral or lateral curvatures which make
penetration more difficult, tend to have lesser degrees of curvature corrected.
Nesbit procedure
The Nesbit procedure was first described in 1965 to
correct congenital penile curvature and an overall success rate of 82% has been
quoted when the procedure is used to correct penile angulation due to Peyronie's
disease. Patients should only be considered for a Nesbit procedure following a
thorough evaluation of the disease history and progression. Once it is
established that the disease has entered the stable phase, full informed consent
should be obtained with particular emphasis placed on the inevitable risk of
penile shortening following the procedure and the risk of erectile dysfunction.
The Nesbit procedure involves a routine circumcision followed by degloving of
the penile skin. A saline artificial erection is induced and the plaque is
located. Bucks fascia is then completely elevated to allow mobilization of the
neurovascular bundle and the urethra. Ellipses of tunica are excised from the
convex surface of the penis opposite the plaque with 1 mm of tunica excised for
every 10 degrees of deformity. The defects are closed with poorly absorbable
sutures (O-PDS) with the knots buried on the inside. Although the long term
results of a Nesbit procedure are good, both short term (within 8 weeks) and
long term failures can present with residual penile deformity. Where failures
require revision surgery it is essential to ensure that the disease is stable
and painless before considering a salvage operation. It is imperative that the
preoperative erectile function is assessed using a combination of vasoactive
agents and colour Doppler ultrasound as patients with preoperative erectile
impairment have a reduced satisfaction rate of 74-77%.
A further technique now commonly used as an adjunct during surgery is known as
corporal plication. This technique uses multiple non-absorbable plication
sutures on the contralateral side of the plaque without the need to excise the
tunica or incise the plaque. These plication sutures are most commonly used in
association with a Nesbit or a Lue procedure to correct small angles of residual
penile deformity. If used in isolation in Peyronie's disease, penile shortening
is inevitable and the long term results are not comparable with a failure rate
of up to 24%.
Tunical Grafting Techniques
Plaque excision and grafting is considered to be an
obsolete operation.
By contrast, the Lue procedure involves incising the plaque followed by grafting
of the defect using an autologous vein patch. Although vein patches from the
dorsal penile vein have been used, the saphenous vein is now used more
routinely. The plaque is incised in the shape of an H and the resulting
rectangular defect is closed using a vein patch which has the endothelium
directed adjacent to the erectile tissue. Recent studies have shown excellent or
satisfactory outcome in 92% of patients.
Penile shortening may still occur, but
to a lesser extent than with a Nesbit procedure. The incidence of postoperative
erectile dysfunction is 5-12%. Following the operation, patients are advised to
abstain from sexual intercourse for a 6-week period. Thereafter, if the recovery
is uncomplicated, they can commence sexual activity. A proportion of these
patients will require the concomitant use of oral PDE-5 inhibitors.
Insertion of a penile prosthesis
The combination of severe erectile dysfunction. and penile deformity due to
Peyronie's disease can be managed by using a penile prosthesis. This is
particularly useful in elderly patients with diabetes related erectile
dysfunction in whom oral pharmacotherapies are unlikely to be successful. If
mild to moderate penile curvature is present, the insertion of a penile
prosthesis can restore penile length as well as correct the penile deformity
with a high rate of success.
John, hope this helps when you see the surgeon, if not email me at mtce2006@yahoo.com