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PATHOLOGY
oF
PEYRONIE'S
DISEASE
Overview
Complaints and findings associated with Peyronie’s disease (the nodule or
bump, the pain, and the curvature) stem from the presence of
the dense inelastic scar or plaque in the connective tissue of tunica
albuginea that covers the corpora cavernosa of the penis.(1-2)
If there is sufficient stretching, pressure or irritation from
the scar toward Buck’s fascia, then pain will develop since
the tunica albuginea does not contain pain nerve fibers. The
scar may cause the penis to be straight but shortened, bent
up, down, or to the side, as well as reduced in circumference,
(or all of these at the same time) often resulting in an erect penis that is soft farther away
from the scar and rigid before it.(3)
You might say that Peyronie’s disease (PD) is all about the scar or
plaque. This appears to be the basic problem in PD: too much scar tissue in response to even a small
injury to the connective tissue of the penis.(4)
This section of the website will discuss the Peyronie’s scar
in some detail. This section is rather technical, but the
most important ideas for a layperson to understand have
been italicized. If you don’t understand or remember the
technical parts, that’s fine, just pay attention to the
italicized sections.
Details of Scar
Development in Peyronie’s Disease
On the cellular level, Peyronie’s disease is associated
with perivascular round cell infiltration of the tunica
albuginea.(5) Micro-injury to the small blood vessels by
trauma from a single injury of great force or multiple
injuries of small force, cause fibrin deposition in a
Peyronie’s scar that are not found in normal or scarred tunica
of men who do not have PD.(6) Peyronie’s plaques consist of
dense collagenous connective tissue with reduced and
fragmented elastic fibers. In about one-third of chronic
cases, demonstrable calcification of the scar develops.(7) The
scar tissue of PD contains excessive amounts of type III
collagen, which happens to be specially inclined to excessive
scar development.(8)
Although there are many possible causes of PD, all
commentators mention the most likely cause to be trauma.
This initiating trauma can be a simple solo event, or trauma that is made worse by
an underlying condition that precipitates the excess
Peyronie’s scar. Hinman and Devine were the first to suggest
that trauma to the erect penis activates the disease in a
susceptible individual. They proposed that significant injury
or repeated minor injury, as in frequent or prolonged bending
or blunt trauma to the erect penis, can cause damage to tiny
blood vessels or capillaries. This results in micro-hemorrhage
into the spaces between layers of the tunica albuginea or even
separation (delamination) at the top and bottom of the penis
where the septum blends with the tubular section of the tunica
albuginea.(9,10,11) Injury to the capillary vessels not only
can cause tiny hemorrhages, but it will reduce lymphatic
drainage in the area of injury causing congestion of blood
flow. This in turn traps tissue fluid, fibrinogen, and toxins
that are by-products of the inflammatory process, called
edema, in, around and between the connective tissue layers of
tunica albuginea. This process can serve as a nexus for a
hematoma, and subsequent inflammatory response with
recruitment of macrophages and polymorphic neutrophils.(6,13,14)
Build-up of cellular debris and lymphatic congestion, common to
injury and clot formation, releases a variety of cytokines, autocoids and vasoactive factors, ultimately causing the
excess fibrotic reaction of PD. This pathophysiologic process
and subsequent scar formation is favored by the unique anatomy
of the multiple layers of the tunica albuginea and the normal
minor blood supply of connective tissue in general. With inflammation
by-products trapped between layers of connective tissue having
a poor blood supply and little lymphatic drainage, the stage
is set for a prolonged recovery from injury to the penis that
can take months or years, and therefore foster the formation
of a Peyronie’s scar or plaque.
Normally, there are three phases of repair to this type of
injury: 1. Enzymatic clean-up of the injured area to
remove cellular debris and toxins. 2. Scar formation,
in which scar will develop to close and secure the wound. 3.
Scar remodeling in which excess scar is removed and
collagen fibers are realigned, creating a smaller, stronger
and more efficient scar. In PD, this process goes crazy.
Proteins are significant components of scar development, such
as fibrin, which activate the specialized cells responsible
for making a scar, known as fibroblasts. Fibrin is also
responsible for activating special chemicals known as
cytokines that activate scar formation. If the cytokines
continue working too long or too well, excess scar formation
and collagen deposition can occur. Collagen is the protein
“glue” that holds cells together. The most important cytokine
responsible for wound healing is Transformation Growth
Factor-beta 1, (TGF-b1), but there are others, such as:
platelet derived growth factor, interleukin 6 & 8, and tumor
necrosis factor and more.
TGF-b1 is found to be elevated in many chronic fibrotic
conditions. The man with PD has been shown to possess a
greater level of TGF-b1 in the scar of the tunica albuginea
than men who do not have this problem. Oxygen suppresses
TGF-b1. TGF-b1 has multiple effects on fibroblast function
by increasing transcription and synthesis of collagen, proteoglycans and fibronectin. In addition, TGF-b1 is found to
increase production of collagenase inhibitors. Also involved
in the wound healing process is a hormone substance called
prostaglandin E1. Oxygen enhances prostaglandin E1, which
causes several reactions in the penis: suppresses production
of collagen, and enhances release of calcium by the smooth
muscles of the penis so that blood flow is increased. Thus it
can be seen that oxygen reduces TGF-b1 and increases
prostaglandin E1, and that this has the combined effect of
reducing collagen (scar) in the penis; lack of oxygen would
therefore increase collagen (scar) formation. The combined
effect of too much TGF-b1 is that it favors scar
development, and reduces the substances that can remove
collagen.(15-17) In PD, defects in overproduction of
collagen and other tissue remodeling mechanisms may result in
an inability to resolve the injury and in overabundant plaque
formation.
Recent research has closely examined scar remodeling, the
third phase of injury repair. Since scar remodeling involves
various enzymes, and protein and collagen are major components
of scar tissue, the protease and collagenase enzymes have been
closely studied. These two enzymes break down the protein and
collagen portion of the immature scar in an effort to reduce
or remodel it. Several protease and collagenase abnormalities
have been discovered in PD: insufficient production, abnormal
structure, and premature destruction. Any of these problems
may contribute to poor scar remodeling, allowing the scar to
grow beyond a normal or useful size. Other recent findings
suggest that other proteins (biglycans, decorin, tenascin and
elastin) are also important in the regulation of collagen
production and deposition within a scar. If they are abnormal in
any way, this can also contribute to abnormal wound healing and
increased scar development.
The conclusion drawn from these recent findings is that a
balance must exist between scar formation and scar reduction
or remodeling. If there is an imbalance in this process then
excess scar formation can occur, as seen in PD. Any therapy
or effort intended to improve the quality, quantity or
effectiveness of the various enzymes, hormones or proteins
involved in scar remodeling might be extremely helpful to PD;
these include: TGF-b1, collagen, collagenase, protease and
fibrin.
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With this brief
background of scar tissue development in PD you can begin to
understand the need for effective treatment directed at
supporting and correcting the abnormal chemistry that leads to
the excess scar formation of PD. In other sections you will
again meet these terms and concepts we just covered.
________________________________________
1. Ehrlich HP.
Scar contracture: cellular and connective tissue aspects in
Peyronie's disease. J Urol 1997;157:316-9.
2. Brock G, Hsu GL, Nunes L, von Heyden B, Lue TF. The anatomy
of the tunica albuginea in the normal penis and Peyronie's
disease. J Urol 1997;157:276-81.
3. Devine CJ Jr. Introduction to the International Conference
on Peyronie's disease. J Urol 1997;157: 272-5.
4. Boston University Institute fir Sexual Medicine –Treating
Peyronie’s Disease – 11/29/03
5. Davis CJ Jr.: The microscopic pathology of Peyronie’s
disease. J Urol, 157: 282-284, 1997.
6. Somers KD, Dawson DM: Fibrin deposition in Peyronie’s
disease plaque. J Urol, 157: 311-315, 1997.
7. Gelbard MK: Dystrophic penile calcification in Peyronie’s
disease. J Urol, 139: 738-740, 1988.
8. Ehrlich HP: Scar contracture: cellular and connective
tissue aspects in Peyronie’s disease. J Urol, 157: 316-319,
1997.
9. Devine CJ Jr., Somers KD, Jordan SG, Schlossberg SM:
Proposal: trauma as the cause of the Peyronie’s lesion. J Urol,
157: 285-290, 1997.
10. Jarow JP, Lowe FC: Penile trauma: an etiologic factor in
Peyronie’s disease and erectile dysfunction. J Urol, 158:
1388-1390, 1997.
11. Devine CJ Jr., Horton CE: Peyronie’s disease. Clin Plast
Surg, 15: 405-409, 1988.
12. Diegelmann RF: Cellular and biochemical aspects of normal
and abnormal wound healing: an overview. J Urol, 157: 298-302,
1997.
13. Van de Water L: Mechanisms by which fibrin and fibronectin
appear in healing wounds: implications for Peyronie’s disease.
J Urol, 157: 306-310, 1997.
14. El-Sakka AI, Hassan MU, Nunes L, Bhatnagar RS, Yen TS, Lue
TF: Histological and ultrastructural alterations in an animal
model of Peyronie’s disease. Br J Urol, 81: 445-452, 1998.
15. El-Sakka AI, Hassoba HM, Chui RM, Bhatnagar RS, Dahiya R,
Lue TF: An animal model of Peyronie’s-like condition
associated with an increase of transforming growth factor beta
mRNA and protein expression. J Urol, 158: 2284-2290, 1997.
16. El-Sakka AI, Hassoba HM, Pillarisetty RJ, Dahiya R, Lue TF:
Peyronie’s disease is associated with an increase in
transforming growth factor-beta protein expression. J Urol,
158: 1391-1394, 1997.
17. Ehrlich HP: Scar contracture: cellular and connective
tissue aspects in Peyronie’s disease. J Urol, 157: 316-319,
1997.
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