Effect of Antiangeogenic Treatment on Peritoneal Endometriosis-Associated Nerve Fibers

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Abstract

Pain, the most common symptom in endometriosis, has been reported in up to 50% of patients. Human peritoneal endometriotic lesions are innervated by nerve fibers that appear to be responsible for much of the pain and local tenderness. A number of studies have shown significantly greater nerve fiber density (NFD) in the peritoneal lesions of patients with painful endometriosis than in those with asymptomatic disease. Deep infiltrating endometriosis is characterized by active angiogenesis, with an extensive vascular net formed by immature blood vessels.

Surgical resection of endometriotic lesions relieves chronic pelvic pain and severe dysmenorrhea in many patients; however, most patients suffer a recurrence within 2 years of surgery. Current medical treatments for endometriosis include combinations of oral contraceptives and progestogens, which significantly decrease NFD in the endometrium and myometrium of women with endometriosis. In an experimental model of endometriosis, treatment with the dopamine agonist cabergoline significantly decreased the formation of new blood vessels in human endometrium fragments that had been implanted in nude mice peritoneum.

The present study was designed to determine whether the antiangiogenic actions of a dopamine agonist in the experimental nude mouse of endometriosis would also reduce nerve fiber growth by inhibiting formation of new blood vessels in the lesions. Human endometrial biopsy fragments obtained from 4 oocyte donors were fixed in the peritoneum of sixteen 5-week-old ovariectomized nude mice Three weeks after the lesions were established, the animals were divided into 2 experimental treatment groups. Lesions were treated with either cabergoline (n = 8; 0.05 mg/kg/d) or vehicle solution (n = 8) for 14 days. The numbers of immature blood vessels and microvascular density in the experimental-endometriosis lesions were assessed by immunofluorescence analysis of von Willebrand factor and vascular smooth muscle cells (α-SMA). Nerve fiber density in the lesions was assessed using immunochemical analysis of protein-gene product 9.5. The presence of mast cells and macrophages in endometriotic lesions was confirmed by immunohistochemistry using blue toluidine staining.

Morphometric techniques were used to quantify the immunofluorescence and immunohistochemical data. Compared with the control lesions, the NFD and number of macrophages and mast cells were decreased significantly in the cabergoline-treated group compared with controls (P < 0.05). The immature blood vessel was also significantly decreased in the treated lesions (P < 0.001).

These findings show that an antiangiogenic dopamine agonist reduces formation of new blood vessels and nerve fiber growth in experimental-endometriosis lesions. The data support the use of dopamine agonists in the medical treatment of endometriosis-associated pelvic pain.

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