Abstract
Context:Ovarian suppression is a common treatment for endometriosis-associated pelvic pain. Its exact mechanism of action is poorly understood, although it is assumed to reflect reduced production/action of estrogens.Objective:The objective of the study was to measure the expression of mRNAs encoded by nociceptive genes in the peritoneum of women with chronic pelvic pain (CPP) with or without endometriosis and to investigate whether estrogens alter nociceptive gene expression in human sensory neurons.Design:The study was performed using human tissue analysis and cell culture.Setting:The study was conducted at a university research institute.Patients:Peritoneal biopsies were obtained from women with CPP and endometriosis (n = 12), CPP and no endometriosis (n = 10), and no pain or endometriosis (n = 5). Endometriosis lesions were obtained from women with endometriosis (n = 18).Main Outcome Measures:mRNAs encoding ion channels (P2RX3, SCN9A, SCN11A, TRPA1, TRPV1) and the neurotransmitter TAC1 were measured in human tissue samples and in human embryonic stem cell-derived sensory neurons treated with estrogens.Results:TRPV1, TRPA1, and SCN11A mRNAs were significantly higher in the peritoneum from women with endometriosis (P < .001, P < .01). TRPV1, SCN9A, and TAC1 were elevated in endometriosis lesions (P < .05). P2RX3 mRNA was increased in the peritoneum of women with CPP, with and without endometriosis (P < .05). Incubation of sensory neurons with 17β-estradiol increased TRPV1 mRNA (P < .01). The estrogen receptor-β-selective agonist 2,3-bis(4-hydroxy-phenyl)-propionitrile increased concentrations of TRPV1, P2RX3, SCN9A, and TAC1 mRNAs.Conclusions:Estrogen-dependent expression of TRPV1 in sensory neurons may explain why ovarian suppression can reduce endometriosis-associated pain. Strategies directly targeting ion channels may offer an alternative option for the management of CPP.
Highlights
Lesions become innervated by small diameter nerve fibers typical of afferent sensory innervation [1], and stimulation of these nerves by the inflammatory milieu within a lesion may be a direct cause of endometriosis
Measurement of mRNAs encoded by TAC1 and nociceptive ion channels revealed differences between tissue samples; TAC1 was elevated only in endometriosis lesions (Figure 1A; P Ͻ .05), and P2RX3 was increased in the peritoneum of women with chronic pelvic pain (CPP), regardless of whether they were diagnosed with endometriosis compared with the peritoneum of healthy women (Figure 1B; P Ͻ .05)
SCN9A (Nav1.7) was elevated in lesions from women with endometriosis (Figure 1C; P Ͻ .05), whereas SCN11A was significantly higher in the peritoneum of women with CPP and endometriosis compared with the peritoneum of and purity assessed using a NanoDrop ND 1000. cDNA was women with CPP alone (Figure 1D; synthesized using SuperScript VILO enzyme (Invitrogen) with P Ͻ .001). mRNA encoded by TRPA1 was significantly
Summary
Medical Research Council Centre for Reproductive Health, The University of Edinburgh, Queens Medical Research Institute, Edinburgh EH16 4TJ, United Kingdom. Context: Ovarian suppression is a common treatment for endometriosis-associated pelvic pain. Its exact mechanism of action is poorly understood, it is assumed to reflect reduced production/action of estrogens
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