Depression and anxiety in patients with endometriosis-associated chronic pain: Neuroimmune mechanisms mediated by inflammatory factors

Table 1 Demographic and clinical characteristics of the study population, n (%)

Characteristic	All participants (n = 200)	With depression (n = 85)	Without depression (n = 115)	P value	With anxiety (n = 102)	Without anxiety (n = 98)	P value
Age (year), mean ± SD	32.7 ± 6.4	33.2 ± 6.1	32.3 ± 6.6	0.325	32.5 ± 6.3	32.9 ± 6.5	0.652
BMI (kg/m2), mean ± SD	24.6 ± 4.3	25.3 ± 4.6	24.1 ± 4.0	0.047a	25.0 ± 4.5	24.2 ± 4.0	0.182
Education level				0.089	-		0.134
Secondary or lower	42 (21.0)	23 (27.1)	19 (16.5)		26 (25.5)	16 (16.3)
College	114 (57.0)	43 (50.6)	71 (61.7)		53 (52.0)	61 (62.2)
Postgraduate	44 (22.0)	19 (22.4)	25 (21.7)		23 (22.5)	21 (21.4)
Marital status				0.762	-		0.518
Single	62 (31.0)	25 (29.4)	37 (32.2)		34 (33.3)	28 (28.6)
Married	122 (61.0)	52 (61.2)	70 (60.9)		59 (57.8)	63 (64.3)
Divorced/separated	16 (8.0)	8 (9.4)	8 (7.0)		9 (8.8)	7 (7.1)
Employment status				0.018a	-		0.042a
Employed	138 (69.0)	51 (60.0)	87 (75.7)		63 (61.8)	75 (76.5)
Unemployed	46 (23.0)	25 (29.4)	21 (18.3)		29 (28.4)	17 (17.3)
Student	16 (8.0)	9 (10.6)	7 (6.1)		10 (9.8)	6 (6.1)
Disease duration (year), mean ± SD	6.8 ± 4.5	7.5 ± 4.7	6.3 ± 4.3	0.059	7.2 ± 4.6	6.4 ± 4.3	0.195
rASRM stage				0.007b	-		0.013a
Stage I (minimal)	28 (14.0)	8 (9.4)	20 (17.4)		10 (9.8)	18 (18.4)
Stage II (mild)	42 (21.0)	13 (15.3)	29 (25.2)		17 (16.7)	25 (25.5)
Stage III (moderate)	76 (38.0)	34 (40.0)	42 (36.5)		42 (41.2)	34 (34.7)
Stage IV (severe)	54 (27.0)	30 (35.3)	24 (20.9)		33 (32.4)	21 (21.4)
Pain severity (VAS), mean ± SD	6.4 ± 2.1	7.3 ± 1.8	5.7 ± 2.0	< 0.001c	7.0 ± 1.9	5.7 ± 2.0	< 0.001c
Previous treatments
Analgesics	178 (89.0)	78 (91.8)	100 (87.0)	0.283	93 (91.2)	85 (86.7)	0.320
Hormonal therapy	142 (71.0)	64 (75.3)	78 (67.8)	0.250	76 (74.5)	66 (67.3)	0.261
Surgery	168 (84.0)	74 (87.1)	94 (81.7)	0.307	88 (86.3)	80 (81.6)	0.364
Infertility	62 (31.0)	32 (37.6)	30 (26.1)	0.078	37 (36.3)	25 (25.5)	0.098

^aP < 0.05.

^bP < 0.01.

^cP < 0.001.

BMI: Body mass index; rASRM: Revised American Society for Reproductive Medicine; VAS: Visual analog scale.

Table 2 Psychological assessment scores of the study population, n (%)

Assessment	All participants (n = 200)	With depression (n = 85)	Without depression (n = 115)	P value	With anxiety (n = 102)	Without anxiety (n = 98)	P value
BDI-II, mean ± SD	16.8 ± 10.5	26.4 ± 8.3	9.6 ± 5.1	< 0.001	22.3 ± 10.6	11.0 ± 7.2	< 0.001
Depression severity							< 0.001
Minimal (0-13)	115 (57.5)	0 (0.0)	115 (100.0)	-	38 (37.3)	77 (78.6)	-
Mild (14-19)	43 (21.5)	43 (50.6)	0 (0.0)	-	30 (29.4)	13 (13.3)	-
Moderate (20-28)	28 (14.0)	28 (32.9)	0 (0.0)	-	22 (21.6)	6 (6.1)	-
Severe (29-63)	14 (7.0)	14 (16.5)	0 (0.0)	-	12 (11.8)	2 (2.0)	-
STAI-state, mean ± SD	41.3 ± 12.6	48.7 ± 11.4	35.9 ± 10.4	< 0.001	51.2 ± 9.1	31.0 ± 6.8	< 0.001
STAI-trait, mean ± SD	43.5 ± 11.8	50.2 ± 10.4	38.6 ± 10.2	< 0.001	52.4 ± 8.5	34.3 ± 7.3	< 0.001
PSQI global, mean ± SD	7.9 ± 3.8	9.8 ± 3.5	6.5 ± 3.4	< 0.001	9.3 ± 3.7	6.4 ± 3.3	< 0.001
Poor sleep quality (PSQI > 5)	138 (69.0)	74 (87.1)	64 (55.7)	< 0.001	84 (82.4)	54 (55.1)	< 0.001
PCS, mean ± SD	22.4 ± 12.6	30.1 ± 11.7	16.8 ± 9.9	< 0.001	28.3 ± 12.1	16.3 ± 10.0	< 0.001
EHP-30 core, mean ± SD	42.6 ± 19.7	54.8 ± 16.9	33.8 ± 16.8	< 0.001	51.5 ± 18.2	33.3 ± 16.7	< 0.001

BDI-II: Beck Depression Inventory-II; STAI: State-Trait Anxiety Inventory; PSQI: Pittsburgh Sleep Quality Index; PCS: Pain Catastrophizing Scale; EHP-30: Endometriosis Health Profile-30.

Table 3 Serum levels of inflammatory markers and brain-derived neurotrophic factor

Biomarker	All participants (n = 200)	With depression (n = 85)	Without depression (n = 115)	P value	With anxiety (n = 102)	Without anxiety (n = 98)	P value
IL-6 (pg/mL), median (IQR)	2.8 (1.6-4.7)	3.9 (2.4–6.1)	2.1 (1.4-3.5)	< 0.001	3.6 (2.1-5.8)	2.2 (1.4-3.6)	< 0.001
IL-1β (pg/mL), median (IQR)	0.9 (0.5-1.6)	1.3 (0.7-2.1)	0.7 (0.4-1.2)	< 0.001	1.2 (0.6-1.9)	0.7 (0.4-1.2)	< 0.001
TNF-α (pg/mL), median (IQR)	3.4 (2.1-5.3)	4.6 (2.8-6.5)	2.7 (1.8-4.2)	< 0.001	4.2 (2.6-6.1)	2.8 (1.8-4.4)	<0.001
CRP (mg/L), median (IQR)	2.6 (1.3-5.1)	3.8 (1.9-6.7)	1.9 (1.0-3.8)	< 0.001	3.4 (1.7-6.2)	2.0 (1.1-3.9)	< 0.001
BDNF (ng/mL), mean ± SD	24.3 ± 8.4	20.7 ± 7.6	26.9 ± 8.0	< 0.001	21.4 ± 7.8	27.3 ± 8.1	< 0.001

IL-6: Interleukin-6; IL-1β: Interleukin-1β; IQR: Interquartile range; TNF-α: Tumor necrosis factor-alpha; CRP: C-reactive protein; BDNF: Brain-derived neurotrophic factor.

Table 4 Correlation matrix of pain severity, inflammatory markers, and psychological symptoms

Variable	1	2	3	4	5	6	7	8	9
1 Pain severity (VAS)	-	-	-	-	-	-	-	-	-
2 BDI-II	0.52a	-	-	-	-	-	-	-	-
3 STAI-state	0.48a	0.65a	-	-	-	-	-	-	-
4 STAI-trait	0.45a	0.68a	0.76a	-	-	-	-	-	-
5 IL-6	0.43a	0.48a	0.41a	0.39a	-	-	-	-	-
6 IL-1β	0.37a	0.42a	0.36a	0.34a	0.58a	-	-	-	-
7 TNF-α	0.40a	0.45a	0.38a	0.36a	0.62a	0.54a	-	-	-
8 CRP	0.35a	0.40a	0.33a	0.31a	0.49a	0.42a	0.45a	-	-
9 BDNF	-0.38a	-0.46a	-0.43a	-0.44a	-0.36a	-0.32a	-0.34a	-0.28a	-

^aP < 0.001.

Values represent Spearman’s correlation coefficients for non-normally distributed variables and Pearson’s correlation coefficients for normally distributed variables. VAS: Visual analog scale; BDI-II: Beck Depression Inventory-II; STAI: State-Trait Anxiety Inventory; IL-6: Interleukin-6; IL-1β: Interleukin-1β; TNF-α: Tumor necrosis factor-alpha; CRP: C-reactive protein; BDNF: Brain-derived neurotrophic factor.

Table 5 Multiple linear regression analyses for predictors of depression and anxiety

Variable	B	SE	β	P value	95%CI
Dependent variable: BDI-II
Constant	24.63	5.42	-	< 0.001	13.95-35.31
Age	0.06	0.09	0.04	0.497	-0.12 to 0.24
BMI	0.14	0.13	0.06	0.289	-0.12 to 0.40
Disease duration	0.15	0.13	0.07	0.245	-0.10 to 0.40
rASRM stage	0.83	0.62	0.08	0.180	-0.39 to 2.05
Pain severity (VAS)	1.32	0.31	0.27	< 0.001	0.71-1.93
IL-6	0.85	0.32	0.17	0.009	0.22-1.48
IL-1β	0.94	0.69	0.09	0.174	-0.42 to 2.30
TNF-α	0.78	0.31	0.16	0.013	0.17-1.39
CRP	0.21	0.19	0.07	0.269	-0.16 to 0.58
BDNF	-0.26	0.07	-0.21	< 0.001	-0.40 to -0.12
PSQI global	0.49	0.16	0.18	0.003	0.17 to -0.81
R2 = 0.57, adjusted R2 = 0.54, F (11-188) = 22.61, P < 0.001
Dependent variable: STAI-state
Constant	51.84	7.61	-	< 0.001	36.83-66.85
Age	0.03	0.13	0.01	0.831	-0.22 to 0.28
BMI	0.17	0.18	0.06	0.351	-0.19 to 0.53
Disease duration	0.18	0.18	0.06	0.310	-0.17 to 0.53
rASRM stage	0.91	0.87	0.06	0.297	-0.81 to 2.63
Pain severity (VAS)	1.79	0.43	0.30	< 0.001	0.94-2.64
IL-6	0.94	0.45	0.15	0.038	0.05-1.83
IL-1β	0.78	0.97	0.06	0.423	-1.13 to 2.69
TNF-α	0.76	0.43	0.13	0.080	-0.09 to 1.61
CRP	0.12	0.26	0.03	0.646	-0.39 to 0.63
BDNF	-0.32	0.10	-0.21	0.001	-0.52 to -0.12
PSQI Global	0.84	0.23	0.25	< 0.001	0.39-1.29
R2 = 0.51, adjusted R2 = 0.48, F (11-188) = 17.83, P < 0.001

β: Standardized regression coefficient; B: Unstandardized regression coefficient; BDNF: Brain-derived neurotrophic factor; BMI: Body mass index; CI: Confidence interval; CRP: C-reactive protein; IL-6: Interleukin-6; IL-1β: Interleukin-1β; PSQI: Pittsburgh Sleep Quality Index; rASRM: Revised American Society for Reproductive Medicine; SE: Standard error; TNF-α: Tumor necrosis factor-alpha; VAS: Visual analog scale.