Hyperalgesia, nerve infiltration and nerve growth factor expression in deep adenomyotic nodules, peritoneal and ovarian endometriosis

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Abstract
BACKGROUND: The aim of this study was to investigate a possible role for nerve growth factor (NGF) in the mechanism of pain and hyperalgesia induced by deep adenomyotic nodules and other forms of endometriosis and to clarify the relationship between endometriotic lesions and the surrounding nerves. METHODS: Endometriotic lesions (deep adenomyotic nodules, peritoneal endometriosis, ovarian endometriosis) and eutopic endometrium were obtained from 51 patients presenting with pain. Patients were allocated to two groups (group 1: patients with a deep adenomyotic nodule (n = 23); group 2: patients with peritoneal and/or ovarian endometriosis but without deep adenomyotic nodule (n = 28). Immunohistochemistry with antibodies against NGF, NGF specific tyrosine-kinase receptor (Trk-A) and S-100 protein was performed. Results were expressed as mean H-scores ± SD, and correlated with the presence of hyperalgesia. RESULTS: The percentage of patients presenting hyperalgesia at physical examination was significantly higher in group 1 (96%) than in group 2 (11%) (P < 0.001). NGF expression was significantly stronger in deep adenomyotic nodules (DAN) than in ovarian (OE) and peritoneal endometriosis (PE), both in the proliferative phase in the glands [DAN: 226 ± 18; OE: 140 ± 9 (P < 0.001); PE: 110 ± 7 (P < 0.001)] and in the stroma [(DAN: 204 ± 21; OE: 125 ± 15 (P < 0.001); PE: 100 ± 9 (P < 0.01)]. NGF expression in DAN is also significantly stronger than in OE and PE in the secretory phase in the glands [DAN:181 ± 32; OE: 85 ± 3.3 (P < 0.001); PE: 65 ± 9 (P < 0.001)] and in the stroma [DAN: 173 ± 28; OE: 85 ± 3.7 (P < 0.001); PE: 35 ± 13 (P < 0.001)]. Perineurial and intraneurial invasion by endometriotic lesions were found only in deep adenomyotic nodules and not in the other forms of endometriosis. The specific receptor for NGF (Trk-A) is expressed in all the nerves that were included in the biopsies. CONCLUSIONS: These results suggest a role of NGF in endometriotic pain and hyperalgesia in deep adenomyotic nodules. The strong expression of the NGF-TrkA pathway in deep adenomyotic nodules could explain why this type of lesion infiltrates in richly innervated anatomical sites.