An integrated multi-tissue approach for endometriosis candidate biomarkers: a systematic review

Brulport, Axelle; Bourdon, Mathilde; Vaiman, Daniel; Drouet, Christian; Pocate-Cheriet, Khaled; Bouzid, Kheira; Marcellin, Louis; Santulli, Pietro; Abo, Carole; Jeljeli, Maxime; Chouzenoux, Sandrine; Chapron, Charles; Batteux, Frédéric; Berthelot, Camille; Doridot, Ludivine

doi:10.1186/s12958-023-01181-8

Reproductive Biology and Endocrinology

Table 1 Biomarkers found in different biological compartments by independent teams

From: An integrated multi-tissue approach for endometriosis candidate biomarkers: a systematic review

Molecular subtypes	Biomarkers found in several tissues	Biological compartments							References by compartment: B for Blood, P for Peritoneum/Peritoneal fluid, E for Endometrium, O for ovary, U for Urine, M for menstrual blood, and Sa for Saliva
		B	P	E	O	U	M	Sa	n = X&Y with X the number of samples from women without endometriosis, Y the number of samples from women with endometriosis
		B	P	E	O	U	M	Sa	Up/Down (in endometriosis patients vs controls) is indicated when studies are inconsistent
Immunity related markers / Cytokines	CXCL8 (IL8)	↑	↑	↑	↓*		↑*		B: [12] n = 93&201; [13] n = 25&19; [14] n = 12&75 P: [15] n = 30&48; [16] n = 16&67; [17] n = 20&57; [18] n = 27&36; [19] n = 40&58; [20] n = 34&124; [21] n = 38&56; [22] n = 45&126; [23] n = 35&45 E: [24] n = 11&24; [25] n = 8&15; [26] n = 5&5 O: [27] n = 9&9 (cumulus cells) – M: [28] n = 3&3
	TNFa	↑↓	↑	↑	↑				B: Up [13] n = 25&19; Up[29]n = 103&190, Down[12]n = 93&201; Down [30]n = 121&232 P: [31] n = 22&30; [32] n = 17&33; [17] n = 20&57; [23] n = 35&45; [33] n = 59&73 E: [24] n = 11&24 – O: [34] n = 279&47 (follicular fluid)
	(s)ICAM-1	↑↓	↑↓	↑	↓*				B: Up [35] n = 20&48; Up [36]n = 48&49; Down [30]n = 121&232; Down [37]n = 86&170P: Up [38] n = 6&12; Up in peritoneal tissue in menstrual phase, Down in luteal phase [24] n = 11&24 E: [26] n = 5&5 – O: [27] n = 9&9 (cumulus cells)
	IFNɣ	↑↓	↑		↓		↑		B: Up [39] n = 68&70; Up [13] n = 25&19; Down [30] n = 121&232 P: [40] n = 30&50; [17] n = 20&57 – O: [41] n = 29&20 (follicular fluid) M: [42] (in the supernatant of menstrual blood derived stem cells with an allogeneic stimulation) n = 6&6
	IL6	↑	↑	↑			↑*		B: [43] n = 72&38; [39] n = 68&70; [44] n = 31&38; [12] n = 93&201; [32] n = 17&33; [13] n = 25&19; [35] n = 20&48; [45] n = 22&47; [46] n = 35&45; [47] n = 60&80; [48] n = 32&40; [49] n = 35&43; [29] n = 103&190; [14] n = 12&75; P: [24] n = 11&24; [31] n = 22&30; [16] n = 16&67; [32] n = 17&33; [50] n = 28&70; [51] n = 42&36; [19] = 40&58; [35] n = 20&48; [45] n = 22&47 [23]; n = 35&45; [46] n = 35&45; [22] n = 45&126; [48] n = 32&40; E: [26] n = 5&5 – M: [28] n = 3&3
	CCL5 (RANTES)	↑	↑	↑					B: [13] n = 25&19 – P: [17] n = 20&57; [52] n = 20&74 – E: [53] n = 5&15
	CXCL10 (IP-10)	↓	↑↓	↑*					B: [54] n = 70&77 – E: [55] n = 8&8 P: [56] Up n = 32&101; [33] Up n = 59&73; Up [38] n = 6&12; [54] Down n = 70&77; [52] n = 20&74

Molecular subtypes	Biomarkers found in several tissues	Biological compartments							References by compartment: B for Blood, P for Peritoneum/Peritoneal fluid, E for Endometrium, O for ovary, U for Urine, M for menstrual blood, and Sa for Saliva
		B	P	E	O	U	M	Sa	n = X&Y with X the number of samples from women without endometriosis, Y the number of samples from women with endometriosis
		B	P	E	O	U	M	Sa	Up/Down (in endometriosis patients vs controls) is indicated when studies are inconsistent
Immunity related markers / Cytokines	IL6R	↓*	↑	↓*					B and P: [45] n = 22&47 – E: [55] n = 8&8
	IL4	↑	↑		↑				B: [13] n = 25&19; [47] n = 60&80 P: [57] n = 31&38; [17] n = 20&57 – O: [41] n = 29&20 (follicular fluid)
	IL17A	↓	↑↓		↓				B: [58] n = 16&27 – P: [52] Up n = 20&74 [22], Down n = 45&126 O: [41] n = 29&20 (follicular fluid)
	IL2	↑↓	↑		↓				B: Up [13] n = 25&19, Down [44] n = 31&38, Down [58] n = 16&27; P: [58] n = 15&27 – O: [59] n = 5&5 (follicular fluid)
	IL13	↑↓	↓		↑				B: Up [13] n = 25&19, Down [60] n = 46&57 P: [21] n = 38&56 – O: [41] n = 29&20
	IL10	↑	↑				↑		B: [13] n = 25&19; [58] n = 16&27; P: [51] n = 42&36; [23] 2018 n = 35&45 – M: [42] n = 6&6
	CCL2 (MCP-1)	↑	↑				↑		B: [61] n = 31&18; [62] n = 60&102; [39] n = 68&70; [29] n = 103&190; P: [56] n = 32&101; [18] n = 27&36; [21] n = 38&56 M: [42] n = 6&6
	IL9, IL37	↑	↑						B: IL37 [58] n = 36&27, IL9: [13] n = 25&19, B and P: [48] n = 32&40 P: IL9 [17] n = 20&57
	GM-CSF	↑	↑		↓*				B: [13] n = 25&19 – P: [17] n = 20&57 – O: [27] n = 9&9
	IL1β	↑↓	↑				↑*		B: Up [13] n = 25&19; [49] Up n = 35&43, Down [30] n = 121&232 P: [31] n = 22&30; [57] n = 31&38; [17] n = 20&57; [33] n = 59&73 M: [28] n = 3&3
	IL12	↑↓	↑						B: Up [13] n = 25&19, Down [60] n = 46&57 – P: [63] n = 33&72, [33] n = 59&73
	FAS/CD95 +	↑↓	↑*						B: [64] Up (soluble) n = 30&30, [40] Down (T cell surface) n = 30&50, P: [65] (in NK cells) n = 24&46; [66] n = 18&26
	IL1α		↑		↑↓*				P: [52] n = 20&74 O: [41] Up n = 29&20 (folicular fluid), [27] Down n = 9&9 (cumulus cells)
	IL3		↓		↑				P [33]: n = 59&73 – O: [41] n = 29&20 (folicular fluid)
	CCL22 (MDC)		↑		↓				P: [52] n = 20&74 – O: [41] n = 29&20 (folicular fluid)
	IL32	↑		↑*					B: [67] n = 35&50 – E: [55] n = 8&8
	CD8 + (cytotoxic T cells)	↓		↑					B: [40] n = 30&50, [68] n = 20&54 – E: [69] n = 15&15
	CD3 + or CD4 + (T cells)	↑	↑ CD3	↑ CD4					B: [40] n = 30&50, [68] n = 20&54 P: [16] = 16&67 E: [69] n = 15&15
	CD25HIGH/FOXP3 + /CD4 + (Treg cells)	↓	↑						B: [70] n = 15&17 P: [70] n = 15&17, [50] n = 28&70; [71] n = 25&25

Molecular subtypes	Biomarkers found in several tissues	Biological compartments							References by compartment: B for Blood, P for Peritoneum/Peritoneal fluid, E for Endometrium, O for ovary, U for Urine, M for menstrual blood, and Sa for Saliva
		B	P	E	O	U	M	Sa	n = X&Y with X the number of samples from women without endometriosis, Y the number of samples from women with endometriosis
		B	P	E	O	U	M	Sa	Up/Down (in endometriosis patients vs controls) is indicated when studies are inconsistent
Immunity related markers / Cytokines	CD68 (macrophages)		↑	↑					P [15]: n = 30&48; [31] n = 22&30; [72] n = 18&38; [45] n = 22&47 E: [73] n = 36&37
	GAL-3		↑	↓					P: [74] n = 8&15 – E: [75] n = 34&34
	PTGS2			↑	↓				E: [76] n = 21&26, O: [77] n = 40&38 (Cumulus cells)
	CXCL12 (SDF-1)	↑			↑*				B: [78] n = 10&11, O: [27] n = 9&9
ECM/Cell Markers/ Cell fate	MMP-9 (or MMP-9/NGAL)	↑	↑		↑	↑	↑*		B: [79] n = 31&60; [80] n = 26&50; [81] n = 140&200 – P [80]: n = 26&50 O: [81] n = 140&200; U: [82] n = 58&73 – M: [28] n = 3&3
	MMP-2				↑	↓	↑*		O: [81] n = 140&200 – U: [83] n = 25&25; M: [28] n = 3&3
	MMP-3	↑	↑	↑					B: [84] n = 20&40; [85] n = 20&40 P: [24] n = 11&24; E: [24] n = 11&24, [86] n = 20&23
	MMP-7		↑	↑					P: [20] n = 34&124; E: [87] n = 110&109
	OSTEOPONTIN, PERIOSTIN	↑	↑	↑					Osteopontin: B and E: [88] n = 41&40 – P: [38] n = 6&12 Periostin: B and P: [89] n = 80&104 – E: [90] n = 11&14
	CA-125 aka MUC-16	↑	↑						B: [25] n = 32&71; [91] n = 37&47; [92] n = 17&35; [93] n = 52&52 P: [94] n = 43&65; [92] n = 17&35; [93] n = 52&52; [25] n = 32&71 [91]; n = 37&47
	CA-19–9	↑	↑						B: [95] n = 36&50; [96] n = 40&60; [91] n = 37&47 – P: [20] n = 34&124
	CYTOKERATIN-19	↑				↑			B: [97] n = 35&44 – U: [97] n = 35&44; [98] n = 6&11
	TIMP-1	↓	↑		↓				B: [81] n = 140&200 – P: [22] n = 45&126 – O: [81] n = 140&200
	FIBRONECTIN			↓	↑				E: [99] n = 18&40 – O: [100] n = 10&20
	TGF-β	↑	↑	↑	↑				B: [81] n = 140&200 – P: [50] n = 28&70 E: [101] n = 10&10 – O: [81] n = 140&200
	BCL2			↑			↑*		E: [102] n = 20&20 – M: [28] n = 3&3
	SOX2			↑			↑*		E: [103] n = 16&26 – M: [28] n = 3&3
Metabolites	GLUTAMINE, ALANINE	↑		↓*	↓				B: Glutamine: [104] n = 15&22; Alanine: [105] n = 23&22 E: [106] n = 24&95 – O: [107] n = 9&7 (samples n = 50&29)
	LYSINE	↑		↑↓		↓			B: [105] n = 23&22 – U: [108] n = 36&45 E: Up [109] n = 29&37; Down [106] n = 24&95
	LEUCINE	↑		↑↓					B: [105] n = 23&22 E Down: [106] n = 24&95; Up: [109] n = 29&37
	ISOLEUCINE	↓			↑				B: [105] n = 23&22 – O: [107] n = 9&7 (samples n = 50&29)
	THREONINE	↑			↓				B: [105] n = 23&22 – O: [107] n = 9&7 (samples n = 50&29)
	VALINE	↑				↑			B: [105] n = 23&22; [110] n = 23&50 U: [108] n = 36&45

Molecular subtypes	Biomarkers found in several tissues	Biological compartments							References by compartment: B for Blood, P for Peritoneum/Peritoneal fluid, E for Endometrium, O for ovary, U for Urine, M for menstrual blood, and Sa for Saliva
		B	P	E	O	U	M	Sa	n = X&Y with X the number of samples from women without endometriosis, Y the number of samples from women with endometriosis
		B	P	E	O	U	M	Sa	Up/Down (in endometriosis patients vs controls) is indicated when studies are inconsistent
Metabolites	TYROSINE			↑	↓				E: [109] n = 29&37; [106] n = 24&95 O: [107] n = 9&7 (samples n = 50&29)
	TAURINE			↑		↑			E: [106] n = 24&95 – U: [108] n = 36&45
	LACTATE, 3-HYDROXYBUTYRATE	↑			↑				B: [105] n = 23&22 O: [107] n = 9&7 (samples n = 50&29)
	GLUCOSE	↓		↑*	↓				B: [29] n = 103&190; [105] n = 23&22 – E [106]: n = 24&95 O: [107] n = 9&7 (samples n = 50&29)
Hormones/ Growth Factors	ERα		↑	↑↓			↑*		P: [31] n = 22&30 – M: [28] n = 3&3 E: [111] Up n = 18&38, [112] Down n = 26&28
	ERβ		↑	↓					P: [31] = 22&30, E [112]: n = 26&28
	LEPTIN	↑	↓*						B: [113] n = 30&30 P: [19] n = 40&58
	AMH	↓		↑*					B: [114] n = 93&57, [115] n = 17&17 – E: [116] n = 20&23
	FGF-2	↑*	↑						P: [52] n = 20&74, [117] n = 18&38
	VEGF/VEGF-A	↑↓	↑	↑*			↑*		B: Up [30] n = 121&232; Up [29] n = 103&190; Up [118] n = 822&1109; Up [119] n = 30&30; Down [25] n = 32&71; Down [60] n = 46&57; P [22]: n = 45&126 – E: [26] n = 5&5 – M: [28] n = 3&3
	PDGF-A		↑*	↓					P: [52] n = 20&74 – E: [25] n = 8&15
	ACTIVIN-A	↑*		↑*					B: [120] n = 75&139 – P: [121] n = 3&6
miRNAs	MIR-451/MIR-451A	↑↓	↑	↑	↓				B: Up [122] n = 24&24; Up [123] n = 99&89; Down [124] n = 66&80 P: [22] n = 45&126 – E: [125] n = 20&40 – O: [126] n = 30&30 (follicular fluid)
	MIR-122, MIR-199A	↑	↑						B: [127] n = 25&60, [46] n = 35&45 – P: [46] n = 35&45
	MIR-15A-5P	↓		↓					B: [128] n = 30&60 – E: n = 3&3
	MIR-17/MIR-17-5P	↓		↓					B: [47] n = 60&80; [128] n = 30&60 – E: [129] n = 51&51
	MIR-135A	↑↓						↑	B: Down [130] n = 24&24; Up [131] n = 17&17 – Sa: [131] n = 17&17
Other	GLYCODELIN-A	↑	↑						B: [37] n = 86&170; [30] n = 121&232 [19]; n = 42&57; [35] n = 20&48 P: [37] n = 86&170; [19] n = 42&57; [32] n = 17&33, [35] n = 20&48
	HAPTOGLOBIN	↓	↑						B: [132] n = 15&15 – P: [133] n = 8&16
	PGP9.5		↑	↑*					P: [72] n = 18&38 – E: [134] n = 20&20

Arrows indicate the direction of change in endometriosis patients. *: change detected only in a subgroup of patients (either because of patient inclusion criteria restricting to a subgroup of patients, or detected only in a specific subgroup of all included patients). ILX Interleukin X, CA-X Cancer Antigen X, MMP-X Matrix Metalloproteinase-X, CDX Cluster of Differentiation X, CXCLX Chemokine (C-X-C motif) ligand X, TNFα Tumor Necrosis Factor alpha, (s)ICAM-1 (soluble) Intercellular adhesion molecule-1, IFNy Interferon gamma, CCL5 Chemokine (C-C motif) ligand 5, IP-10 Interferon gamma induced protein 10, IL6R Interleukin 6 receptor, MCP-1 Monocyte Chemoattractant protein-1, GM-CSF Granulocyte/macrophage-colony stimulating factor, MDC Macrophage-derived chemokine, GAL-3 Galectin-3, VEGF Vascular Endothelial Growth Factor, NGAL Neutrophil Gelatinase-Associated Lipocalin, TIMP-1 TIMP metallopeptidase inhibitor-1, MUC-16 Mucin-16, TGF-β Transforming growth factor beta, BCL2 B-cell lymphoma 2, ERα Estrogen receptor alpha, ERβ Estrogen receptor beta, AMH Anti-Müllerian hormone, FGF-2 Fibroblast growth factor 2, PDGF Patelet-derived growth factor, PGP9.5 Protein gene product 9.5, PTGS2 Prostaglandin-endoperoxide synthase 2, SDF-1 Stromal cell-derived facotr-1.

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