Disease Severity- and Hormonal Status-Dependent Alterations of EGF and MIF in the Serum of Endometriosis Patients

Abstract

Endometriosis is the extrauterine engraftment of endometrium-like tissue, causing chronic pain. Complex sensory-vascular-immune interactions, including growth factors, cytokines, and neuropeptides, are implicated in its pathophysiology, but the mechanisms remain unknown. Here, epidermal growth factor (EGF), vascular endothelial growth factor, interleukins (IL-1β, IL-6, IL-8), macrophage migration inhibitory factor (MIF), calcitonin gene-related peptide, and somatostatin were measured in the serum of endometriosis patients with different disease severities, menstruation cycle- and pharmacotherapy-related hormonal status compared with controls. Mediator levels in deep-infiltrating rectosigmoid nodules were also compared with those in non-endometriotic colon tissues. Pain was assessed by the visual analogue scale. Serum EGF was significantly lower in mild endometriosis and in the secretory phase. MIF and IL-6 were higher in stage I-IV endometriosis, with MIF also higher in the secretory phase and in patients not receiving oral contraceptives. Somatostatin was lower in mild endometriosis than that in healthy individuals and the severe endometriosis group. No tissue-level differences were found. A strong positive correlation between serum EGF and somatostatin levels and dysmenorrhea and dysuria was detected in mild cases. It is concluded that certain serum alterations may be related to severity- and hormone status-dependent endometriosis mechanisms, but their diagnostic/prognostic value seems to be limited due to variability and lack of specificity.

Keywords: calcitonin gene-related peptide; endometriosis; immunoassay; interleukins; macrophage migration inhibitory factor; pain assessment; somatostatin; systemic inflammation; tumor necrosis factor alpha; visual analogue scale.

Figure 1

Serum levels of (A) epidermal growth factor (EGF) and (B) vascular endothelial growth factor (VEGF) in endometriosis patients compared with healthy individuals. Horizontal lines representing the means ± SEM are demonstrated together with individual data points in a scatter plot. Abbreviations: COCs: combined oral contraceptives; NC: no cycle, NOCs: no oral contraceptives; PROG: progesterone; PROL: proliferative phase of menstrual cycle; SEC: secretory phase of menstrual cycle. p < 0.05; * vs. CTRL group (respective cycle if applicable): # vs. proliferative cycle of respective group; $ vs. NC group (Mann–Whitney U-test (CTRL vs. Endo), Kruskal–Wallis + Benjamini–Hochberg post hoc test (rest of the comparisons)).

Figure 2

Serum levels of (A) macrophage migration inhibitory factor, (B) interleukin 6, (C) interleukin-1β, (D) interleukin 8, and (E) tumor necrosis factor α in multiple comparisons between control and endometriosis samples. Horizontal lines representing the means ± SEM are demonstrated together with individual data points in a scatter plot. Abbreviations: COCs: combined oral contraceptives; NC: no cycle, NOCs: no oral contraceptives; PROG: progesterone; PROL: proliferative phase of menstrual cycle; SEC: secretory phase of menstrual cycle. **: p < 0.01; * p < 0.05; Mann–Whitney U-test (CTRL vs. Endo), Kruskal–Wallis + Benjamini–Hochberg post hoc test (rest of the comparisons).

Figure 3

Serum levels of (A) somatostatin and (B) calcitonin gene-related peptide in multiple comparisons between control and endometriosis samples. Horizontal lines representing the means ± SEM are demonstrated together with individual data points in a scatter plot. Abbreviations: COCs: combined oral contraceptives; NC: no cycle, NOCs: no oral contraceptives; PROG: progesterone; PROL: proliferative phase of menstrual cycle; SEC: secretory phase of menstrual cycle. p < 0.05; *: vs. ctrl; # vs. mild endometriosis group; Mann–Whitney U-test (CTRL vs. Endo), Kruskal–Wallis + Benjamini–Hochberg post hoc test (rest of the comparisons).

Figure 4

Tissue levels of (A) epidermal growth factor, (B) vascular endothelial growth factor, (C) macrophage migration inhibitory factor, (D) tumor necrosis factor α, (E) interleukin-1β, (F) interleukin 6, (G) interleukin-8, and (H) somatostatin in comparisons between healthy bowel wall (n = 4) and deep-infiltrating rectosigmoid endometriosis (DIER; n = 12) samples. Horizontal lines representing the means ± SEM are demonstrated together with individual data points in a scatter plot; Mann–Whitney U-test.