Pathology of Peyronie’s Disease – What goes on under the skin

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 natural treatment 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)    The Peyronie’s plaque consists 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)

	Collagen in normal tissue of the tunica albuginea. Organized collagen fibers arranged in sheets that slide past each other during expansion and contraction of the erection process.
	Collagen in Peyronie’s disease. Densely packed collagen fibers prevent normal siding of tissue during expansion and contraction of erection process, resulting in a curved penis or other familiar distortion (niche, ding, bottleneck, hourglass, etc.)

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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.
 

Commentary:  Standard medical "wait-and-see treatment" of Peyronie’s disease, click Peyronie’s Disease and Man Whose House is on Fire.
 

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. With this brief background of scar tissue development you can begin to understand the need for effective Peyronie’s disease 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.