The excessive expression of BDNF and TrKB in malignant tumors will promote the development of tumor. Though endometriosis is a benign disease, the extensive lesions, strong invasiveness and reoccurrence make its biological behavior have many similarities to malignant tumors. The most characteristic symptom is pelvic pain, including dysmenorrhea and chronic pelvic pain(5). BDNF plays an important role in the visceral pain and high sensitivity (6). Therefore, it needs to be further discussed whether there is a correlation between BDNF, TrKB and the development of endometriosis and endometriosis-related dysmenorrhea.
BDNF was belonged to the neurotrophin (NT) family, which is a small molecular polypeptides growth factor. BDNF exert their functions through engagement of Trk tyrosine kinase receptors, which can active activate downstream pathways to enhance cell survival and growth. The most predominant receptor is TrkB.
There are many theories on pathogenesis of endometriosis, but the menstrual blood reflux theory proposed by Sampson still occupies the leading position (5). A research found that BDNF was detected in menstrual blood and endometrium in reproductive female with quantitative analysis showing that the concentration of BDNF in menstrual blood is higher than in plasma (7), which indicated BDNF may play a role in female reproductive function. The expression of TrKB increased in eutopic endometrium of patients with endometriosis and TrKB was considered to be one of the most potent growth factors for inhibiting anoikis (8). Binding BDNF to TrKB, or activating PI3K pathway can inhibit proapoptotic protein activation and activate antiapoptotic protein Bcl-2 (9); or activating MAPK signaling pathway can influence transcription factor and activate Bcl-2 (10); co-inhibit shedding endometrium from anoikis. Our study found that there was a significant difference in the expression of BDNF and TrKB between endometriosis endometrium and non-endometriosis endometrium, which is consistent with literature reported (11, 12). Moreover, this study showed that the expression of BDNF and TrKB in ovarian endometriotic lesions was higher than that in eutopic endometrium, which is similar to Borghese et al. who found that the expression of BDNF in ovarian endometriotic lesions was higher than that in eutopic endometrium. This suggest that BDNF and TrKB may be involved in the pathogenesis of endometriosis.
Previous studies have found that in mice, estrogen exposure after ovariectomy significantly upregulated BDNF, but the hormonal fluctuations of the murine estrous cycle did not (13); detecting the plasma BDNF concentration of endometriosis patients by ELISA found that menstrual period did not affect the expression BDNF, either (14); other researches believed that the expression of TrKB in eutopic endometrium has no correlation with menstrual period (15). Our results suggested that there was no significant difference statistically of the expression of BDNF and TrKB between proliferative and secretary phases in both ovarian endometriotic lesions and eutopic endometrium of endometriosis patients.
The study also found that there was a significant difference in degree of adhesion and infiltration depth between different stages of endometriosis, and the degree of adhesion and infiltration depth also increased with the increase of stages. Results of our study showed that the expression of BDNF and TrKB in ovarian ectopic lesions and eutopic endometrium increased with the increase of r-AFS stage, speculating that BDNF and TrKB may be correlated with severity of endometriotic lesions. The expression of BDNF and TrKB increased with the increase of stages and resulted in neogenesis of ectopic lesions and aggravated progression of the original lesions continuously, through inhibiting anoikis, promoting cell invasion, proliferation and angiogenesis and so on. Meanwhile, the study demonstrated that ectopic lesions can synthesize BDNF continuously (16, 17), thus forming a vicious cycle and further leading to the aggravation of the disease.
Consistent with previous studies, We found that the expressions of BDNF and TrKB in ovarian endometriotic lesions was no correlation with dysmenorrhea VAS score (18). Meanwhile, We also found that there was a moderate positive correlation between the expression of BDNF, TrKB in eutopic endometrium and dysmenorrhea VAS score. Therefore we can speculate the characteristics of eutopic endometrium play a key role in endometriosis dysmenorrhea and the effect caused by molecular biological changes of eutopic endometrium on the genesis of endometriosis dysmenorrhea may be larger than that caused by ovarian endometriotic lesions, speculating that BDNF and TrKB may be correlated with endometriosis dysmenorrhea. The significant increase of BDNF in endometriosis and abnormal distribution of different types of nerve fibers may be the causes leading to endometriosis pain. The joint effect of BDNF, vascular growth factor and immune inflammation factor are involved in peripheral nerve sensitization caused by chronic activation of nerve endings. Pelvic visceral pain can transfer to brainstem via vagus nerve, or to sacral dorsal commissural nucleus via pelvic nerve, where existing the high expression of K+-Cl-cotransporter2 (KCC2). The high expression of KCC2 or the decrease of ion transportation activity will destroy the stability of Cl- in nerve cells, causing γ-aminobutyric acid (GABA) nerve deinhibition, thus leading to hyperpathia (19).
This study further validated the effect of BDNF/TrKB signaling pathway on the process of endometriosis and analyzed its expression changes, combined with the degree of dysmenorrhea, in different parts of the endometrium at different stages. BDNF is produced by BDNF precursor (proBDNF) cleavage intercellularly or by secreting to extracellular space followed by protease cleavage. The low-affinity receptor of BDNF, p75 receptor, has a high affinity for proBDNF, but a low affinity for BDNF. Binding proBDNF to P75 receptor can activate the pro-apoptotic signaling pathway. Binding BDNF to its high-affinity receptor TrKB can activate MAPK pathway, PI3K/AKT pathway and PLCγ pathway, exerting various effects of inhibiting anoikis (20, 21), autophagocytic defect (22, 23), angiogenesis (3, 24), cell invasion and proliferation (20, 22, 25) and highly expressing in various malignant tumors (26), which, has been the focus of tumor researches recently (Figure 5A).
Pelvic pain is the most typical clinical symptom in endometriosis, but the exact mechanism remains unclear yet. At present three main mechanisms causing pain include: the close connection between lesions and surrounding nerves, specific inflammatory environment and the effect of central nerve system in pain (27). As an important member of NT family, BDNF exerts a key effect in growth, differentiation and survival of nerve fibers (26), and in visceral pain and high sensitivity (19). A research found that there were no nerve cells in endometriotic lesions originally, but BDNF and NGF can promote the generation of nerve tissue in endometriotic lesions (28) and the expression level of BDNF and NGF is correlated with pain degree of endometriosis patients (29). However, another study showed that the expression level of BDNF and NGF was no significant correlation with the degree of pain (30). The manifestations of endometriosis pain in different types and locations are varying and the mechanisms are different between peritoneal endometriosis and deep infiltrating endometriosis (DIE), the former may be correlated with the stimulation of cytokines and growth factor generated by lesions, while the latter is correlated with stimulation of various factors, as well as the deep lesions as reported in previous study (31) (Fig. 5 B).
Whereas our previous study was exploratory with small sample size, and lack of r-AFS stage I patients when collecting samples and the little number of r-AFS stage II due to preliminary exploratory research. Further, we will expand the sample size, and systematically explore the mechanism of Neurotrophin / Trk signaling pathway and its effect on endometrium and nerve fiber cells.