Increased serum levels of mBDNF in women with minimal and mild endometriosis have no predictive power for the disease

Abstract

The objective of our pilot clinical, prospective study was to determine the serum levels of mature brain-derived neurotrophic factor, in of women with endometriosis and controls and explore whether mature brain-derived neurotrophic factor is a potential biomarker for the disease. The patients were selected from the Endometriosis Marker Austria prospective cohort study conducted at the tertiary referral certified Endometriosis Center of the Medical University of Vienna. All women underwent laparoscopic surgery because there was a suspicion of endometriosis, or the women had pelvic pain, adnexal cysts, unexplained infertility, or uterine fibroids. Our main outcome parameter was total levels of mature brain-derived neurotrophic factor in serum, measured using ELISA. Our results show that serum levels of mature brain-derived neurotrophic factor are significantly higher in women with endometriosis compared to women without endometriosis. The mean serum protein levels are significantly higher in women with rAFS stage I and II endometriosis, whereas no difference was found in women with stage III and IV endometriosis and controls. Postoperative follow-up at 6-10 weeks revealed that surgical intervention leads to equilibration of the levels of secreted mature brain-derived neurotrophic factor between women with and without endometriosis. The difference between serum mature brain-derived neurotrophic factor levels of women with endometriosis compared to women without endometriosis is independent of menstrual cycle phase and overall self-reported pelvic pain. ROC-curve analysis showed that, the mature brain-derived neurotrophic factor is not a useful biomarker for endometriosis. In conclusion, although women with stage I and II endometriosis have increased levels of mature brain-derived neurotrophic factor in serum compared to controls, the difference is not predictive for the disease. Impact statement Endometriosis is a disease that can have a significant impact on the quality of life of affected women. The gold standard for diagnosis to this day remains visualization through laparoscopic surgery with histological verification. Current studies are attempting to find a biomarker with high sensitivity and specificity, which would bypass the surgery-associated risks and would significantly reduce costs. In an attempt to elucidate whether mature serum BDNF can serve as diagnostic marker for the disease, we compared the levels of the protein in women with endometriosis to endometriosis-free controls. While our results showed that serum concentrations of the mature protein were significantly higher in women with endometriosis, we did not find this marker to have the sensitivity or specificity needed in order to allow a reliable diagnosis.

Challenges in uncovering non-invasive biomarkers of endometriosis

“…Many studies have examined candidate biomarkers in accessible body fluids (primarily blood) based on current knowledge of the pathogenesis of endometriosis, as has been well summarized by previous reviews (Figure 1(b)). 12,31,32 We used this strategy to test the applicability of the differences in the levels of secretion of the adhesion molecules VCAM-1 and ICAM-1, 11 pain regulatory protein BDNF, 33 and the regulators of inflammation (soluble CD40 Ligand and CXCL1) 34 in the serum of women with and without endometriosis. However, only one of the three studies validated our initial hypothesis.…”

Neurotrophins and glial cell line-derived neurotrophic factor in the ovary: physiological and pathophysiological implications

“…Data obtained from clinical samples showing that plasma concentrations of BDNF were significantly higher in women with endometriosis (Stages I and II) (Wessels et al , 2016; Rocha et al , 2017; Perricos et al , 2018) may indicate the potential use of BDNF in diagnosing this chronic disease in its early stage. The participation of NGF signaling in the development of ovarian cancer and the findings that NGF and TrkA are highly expressed in women with EOC suggest that NGF may be applied as a biomarker for ovarian cancer.…”

“…Furthermore, the estrogen-induced upregulation of BDNF and TrkB that enhances the proliferation of endometrial cells in uterine tissue has been proposed to explain the pathogenesis of estrogen-dependent diseases, including endometriosis (Wessels et al , 2015; Dong et al , 2017). Indeed, recent clinical studies have reported that plasma concentrations of BDNF were significantly higher in women with endometriosis, especially in Stages I and II disease, indicating that BDNF is a potential clinical marker for this painful disorder during its early stage (Wessels et al , 2016; Rocha et al , 2017; Perricos et al , 2018). Targeted genetic association analysis of a case-control study including 425 patients with endometriosis revealed the presence of a BDNF SNP that was linked to an increased severity of endometriosis (Stage III and Stage IV) (Zhang et al , 2012).…”

Factors affecting stability of plasma brain-derived neurotrophic factor

“…Indeed, women with endometriosis have elevated circulating BDNF concentrations compared to women without disease 19 – 21 , which correlated with pelvic pain 21 , and decreased after surgical removal of lesions 19 . However the clinical value of BDNF as a marker of endometriosis has also been challenged 21 , 22 . While some studies find BDNF to be a useful clinical marker of endometriosis or certain endometriotic lesion types 19 – 21 , others find the difference in BDNF between women with and without endometriosis is not predictive of disease 21 , 22 .…”

“…However the clinical value of BDNF as a marker of endometriosis has also been challenged 21 , 22 . While some studies find BDNF to be a useful clinical marker of endometriosis or certain endometriotic lesion types 19 – 21 , others find the difference in BDNF between women with and without endometriosis is not predictive of disease 21 , 22 . The reasons for variable and divergent findings between studies is difficult to resolve, but could include the fact that some studies quantified BDNF in plasma whilst others used serum, or that different ELISA kits were used for quantification.…”