The Sex Series – Part Six: Male pelvic dysfunction and mast cells

Chronic pelvic pain syndrome (CPPS) affects about 15% of male patients and 90% of patients with chronic prostatitis. Patients with these conditions experience pain in the pelvis, abdomen and genitalia, as well as urinary tract symptoms without evidence of infection. Pain can be intermittent or constant, and can interfere with daily activities including sitting, standing, urination and defecation.

CPPS also causes sexual symptoms. Painful ejaculation, erectile dysfunction, and other types of ejaculation dysfunction are all common in this patient group.  In one study, 40% of patients with CPPS were found to have erectile dysfunction.  In another, 72% of patients reported either erectile dysfunction or difficulty with ejaculation.

Pelvic floor dysfunction is a component of CPPS. Many of these patients have abnormally tense pelvic floor muscles, which can cause muscle spasm and obstruct bloodflow. CPPS patients are more likely than healthy controls to have vascular dysfunction associated with nitric oxide level. In a group of 146 patients with CPPS and verified pelvic floor spasm, 56% experienced painful ejaculation.  Visceral and myofascial pain and spasm of the muscles in the pelvic floor contribute to CPPS.  While pelvic floor dysfunction has been well researched for female patients, there are far fewer studies on pelvic floor dysfunction in men.  Biofeedback and pelvic floor physical therapy can resolve issues with erectile dysfunction and other sexual issues.

IL-17, expressed by special T cells called Th17 cells, is required to develop CPPS-like conditions in animal models. IL-17 triggers mast cell degranulation and secretion of many inflammatory molecules.  A number of mast cell mediators are elevated in patients with CPPS. IL-1b, TNF, IL-6 and IL-8 are higher in seminal fluid of these patients.  CCL2 and CCL3 expression is also increased. In the prostate of animals with a CPPS model, TNF, IL-17a, IFN-γ and IL-1b are all increased.

Tryptase has been found to induce pelvic pain. Levels of tryptase and carboxypeptidase A3 are higher in CPPS patients than in healthy controls.  Tryptase binds to a receptor called PAR2.  When tryptase binds to this PAR2 receptor, it is thought that it makes nerves oversensitive. If the PAR2 receptor is blocked, pelvic pain is mitigated.  In animal models where they cannot make tryptase-like products, pelvic pain does not develop in CPPS.

Nerve growth factor (NGF) is a mast cell mediator that has been implicated in CPPS. It is elevated in seminal plasma of CPPS patients and directly correlates with pain level. It is thought that NGF makes the peripheral nerves oversensitive and causes more nerve cells than usual to be present. NGF and tryptase were elevated in prostate secretions of most CPPS patients in a small patient group. Of note, NGF release occurs and increases weeks after initial symptoms.

In animal models, injecting cetirizine (H1 antihistamine) into the peritoneal cavity decreased pain by about 13.8%; ranitidine (H2 antihistamine), 6.1%; cromolyn, 31.4%. A combination of all three decreased pain by 69.3%. When cromolyn and cetirizine were used together, larger pain relief was achieved than when used individually, but this was not seen when using ranitidine and cromolyn together.  These data suggest that H2 signaling is not a major contributor in chronic pelvic pain in male patients.

Pelvic floor dysfunction is also common in heritable connective tissue diseases and is often present in hypermobile patients.

References:

Done JD, et al. Role of mast cells in male chronic pelvic pain. Journal of Urology 2012: 187, 1473-1482.

Roman K, et al. Tryptase-PAR2 axis in experimental autoimmune prostatitis, a model for chronic pelvic pain syndrome. Pain 2014: 155 (7), 1328-1338.

Cohen D, et al. The role of pelvic floor muscles in male sexual dysfunction and pelvic pain. Sex Med Rev 2016; 4, 53-62.

Murphy SF, et al. IL17 mediates pelvic pain in experimental autoimmune prostatitis (EAP). PLoS ONE 2015, 10(5) : e0125623.