. 2021 May 5;41(4):2489–2564. doi: 10.1002/med.21802

Table 3.

Pathways and molecular targets of current and potential pharmaceuticals for endometriosis treatment

Pathways	Molecular targets	Pathophysiology	Medication	PK and toxicity profile (accession number if available)^a	Drug development approach^b	Original purpose of drugs before EM (phase, start/stated year)^c	Type/Class^d	Clinical stages as EM treatment
Current medication
COX‐2	COX‐1, COX‐2, PPAR‐γ	Proliferation	Indomethacin	PK/toxicity (DB00328)^h	Repurpose	Anti‐inflammatory Agent (since 1963)	Nonhormone, NSAID	Preclinical, off‐label prescription
COX‐2/PGE₂, COX‐2/VEGF	COX‐2	Proliferation and apoptosis	Celecoxib	PK/toxicity (DB00482)^h	Repurpose	Arthritis (IV, 2002)	Nonhormone, NSAID	Preclinical, off‐label prescription
NF‐κB	TNF‐α	Proliferation and inflammation	GnRH agonist	PK/toxicity (DB11979, DB00050)^h	Repurpose	Contraceptive agents (since 1978)	Hormone, GnRH agonist	Phase 4, on‐label prescription
TNFα/NF‐κB	NF‐κB	Proliferation and inflammation	Progesterone or dienogest or danazol	PK/toxicity (DB00396, DB09123, DB01406)^h	Repurpose	NA	Hormones, progestogen & contraceptives	Phase 4, on‐label prescription
VEGF and IL‐8 mediated apoptosis	GnRH	Apoptosis and inflammation	Leuprolide acetate	PK/toxicity (DB00007)^h	Repurpose	Prostate cancer (since 1985)	Hormone, GnRH agonist	Phase 4, on‐label prescription
PI3K/Akt/mTOR and MEK1/2/ERK1/2	AKT and ERK1/2	Apoptosis and autophagy	Dienogest	PK/toxicity (DB09123)^h	Repurpose	Oral contraceptive (III, 2003)	Hormone, progestogen	Phase 3, on‐label prescription
Antiproliferation and proapoptotic agents
CASP and apoptotic proteins effects	NF‐κB, IκB, JNK, p38 MAPK	Proliferation and apoptosis	BAY11‐7085	No information	New	NA	Nonhormones, NF‐κB inhibitor	Preclinical
CASP	MMP‐3	Apoptosis	Melatonin	PK/toxicity (DB01065)^h	Repurpose	Insomnia (IV, 2007), chemotherapy‐induced toxicity (III, 2007), prevention of lung cancer (III, 2007)	Hormone, miscellaneous anxiolytics, sedatives, and hypnotics	Phase 2
E₂/ER	ERβ	Proliferation, inflammation, angiogenesis, and apoptosis	Chloroindazole	No information	New	NA	Nonhormones, NA	Preclinical
E₂/ER	ERα	Proliferation, inflammation, angiogenesis, and apoptosis	Oxabicycloheptene sulfonate	PK (DB04574)^h	New	NA	Nonhormone, NA	Preclinical
E₂/ER	ESR1	Proliferation	Resveratrol	PK/toxicity (drugs.com/resveratrol.)ⁱ	Repurpose	Inflammation in type 2 diabetic patients (III, 2013), Anti‐inflammatory and antioxidant effects (III, 2011)	Natural products, phytoalexin	Phase 4
E₂/ER/VEGF	/	Proliferation and angiogenesis	EGCG	PK ⁶⁷ /toxicity ⁶⁸	Repurpose	Multiple sclerosis (III, 2009), cervical cancer (II, 2005), prostate cancer (II, 2004)	Natural products, catechin	Phase 2
ER stress	TRAIL	Apoptosis	Tunicamycin	Toxicity ⁷¹	New	NA	Nonhormones, antibiotic	Preclinical
Hypoxia/LATS1/YAP1	YAP1	Proliferation, angiogenesis, and migration	Verteporfin	PK/toxicity (DB00460)^h	Repurpose	Neovascular macular degeneration (IV, 2014), polypoidal choroidal vasculopathy (IV, 2008)	Nonhormone, photosensitizing agent	Preclinical
NF‐κB	TNF‐α‐induced effect	Apoptosis and angiogenesis	Ginsenoside Rg3	PK ⁷⁶ /Toxicity ⁷⁷	Repurpose	Endothelial Function (II, 2007)	Natural product, Steroid glycoside	Preclinical
p53/NF‐κB	MMP‐3	Apoptosis	Curcumin	PK/toxicity (DB11672)^h	Repurpose	Inflammation in endometrial carcinoma (II, 2013), irritable bowel syndrome (IV, 2008)	Natural products, curcuminoid	Recruiting
NF‐κB and COX‐2	TGF‐β	Apoptosis	Genistein	PK ⁸²	Repurpose	Endothelial function (III, 2010), vascular and skeletal protective in menopause women (III, 2003), prostate cancer (III, 2003)	Natural product, isoflavone	Preclinical
RAF/MEK/ERK and VEGF/VEGFR	RAF and VEGFR	Proliferation, inflammation, and angiogenesis	Sorafenib	PK/toxicity (DB00398)^h	Repurpose	Hepatocellular carcinoma (IV, 2010) carcinoma, renal cell (III, 2003)	Nonhormone, multikinase inhibitor	Preclinical
MAPK/ERK	BARF	Proliferation and apoptosis	Vemurafenib	PK/toxicity (DB08881)^h	Repurpose	Malignant Melanoma (III, 2010)	Nonhormone, kinase inhibitor	Preclinical
MAPK/PR	MEK1/2	Proliferation and apoptosis	U0126	PK ⁹⁰	New	NA	Nonhormone, MAPK/ERK kinase	Preclinical
MAPK/ERK1/2	ERs	Proliferation	Puerarin	PK ⁹²	Repurpose	Alcohol abuse (II, 2009)	Natural product, isoflavonoid	Preclinical
EGFR/ERK1/2, AKT, B‐catenin, NF‐κB	EP2 and EP4 receptors	Apoptosis	PGE₂ inhibitors	PK/toxicity (DB00917)^h	Repurpose	Cataracts (IV, 2007)	Nonhormone, PGE2 inhibitors	Preclinical
mTOR/Akt	CB1 or CB2	Proliferation, fibrogenesis, and oxidation	WIN 55212‐2	PK ⁹⁶	New	NA	Nonhormone, cannabinoid receptor agonist	Preclinical
Akt/PR	AKT	Proliferation and apoptosis	MK2206	No information	Repurpose	Recurrent ovarian carcinoma (II, 2012), endometrial adenocarcinoma (II, 2012)	Nonhormone, AKT inhibitor	Preclinical
p53, p21, CASP, FOXO, inducing apoptosis	/	Proliferation and apoptosis	Propofol	PK/toxicity (DB00818)^h	Repurpose	Anaesthesia (IV, 2001)	Nonhormone, aesthetic	Preclinical
Metabolic process	PDH kinase	Proliferation	Dichloroacetate	PK ¹⁰¹ /Toxicity (DB08809)^h	Repurpose	Brain cancer (II, 2007), lactic acidosis (III, 1998)	Nonhormone, alpha‐halocarboxylic acid	Preclinical
Autophagy modulators
ATG regulated autophagy	/	Autophagy, proliferation, and apoptosis	MK2206 and chloroquine	NA	NA	NA	Combination therapy; AKT inhibitor (MK2206) and amebicide (chloroquine	Preclinical
E₂/ER and PR	ERα and PRα	Autophagy and inflammation	Ginsenoside PPD	PK ⁷⁶ /Toxicity ⁷⁷	Repurpose	Endothelial Function (II, 2007)	Natural product, Steroid glycoside	Preclinical
ERK and Beclin1 inducing autophagy, CDK	Beclin‐1 and ERK autophagy‐promoting proteins, p27	Proliferation, apoptosis, and autophagy	MIS	No information	Repurpose	PCOS (III, 2012)	Hormone, glycoprotein hormone	Preclinical
Antimigration, anti‐invasion, and antifibrosis agents
CBP/β‐catenin	CBP/β‐catenin complex	Proliferation, migration, apoptosis, and fibrogenesis	C‐82	PK ¹⁰⁵	Repurpose	Systemic scleroderma (II, 2015), psoriasis (II, 2015)	Nonhormone, β‐catenin inhibitor	Preclinical
CBP/β‐catenin	CBP/β‐catenin complex	Proliferation, migration, apoptosis, and fibrogenesis	ICG‐001	No information	Repurpose	Myeloid Leukaemia (II, 2012)	Nonhormone, β‐catenin inhibitor	Preclinical
Wnt/β ‐catenin	Tcf/β‐cateini complex	Proliferation, migration, and invasion	PKF115‐584	No information	New	NA	Natural product, NA	Preclinical
Wnt2/β‐catenin	/	Invasion	Metformin	PK/toxicity (DB00331)^h	Repurpose	PCOS (IV, 2003), type 2 diabetes (IV, 2000)	Nonhormone, antidiabetics and biguanides	Preclinical
Wnt/β‐catenin	Tcf/β‐cateini complex	Proliferation, migration, invasion, and fibrogenesis	PKF115‐584/CGP049090	No information	New	NA	Natural product, NA	Preclinical
TGF‐β1‐stimulated activation of MAPK and Smad pathway	/	Proliferation, migration, invasion, and fibrogenesis	EGCG	PK ⁶⁷ /toxicity ⁶⁸	Repurpose	Multiple sclerosis (III, 2009), cervical cancer (II, 2005), prostate cancer (II, 2004)	Natural product, catechin	Phase 2
NF‐κB/MMP‐2/MMP‐9	NF‐κB	Invasion	Genistein	PK ⁸²	Repurpose	Endothelial Function (III, 2010), vascular and skeletal protective in menopause women (III, 2003), prostate cancer (III, 2003)	Natural product, isoflavone	Preclinical
Rho/ROCK	ROCK	Proliferation, apoptosis, contractility, and differentiation	Fasudil	PK ¹¹³	Repurpose	Raynaud, scleroderma (III, 2007)	Nonhormone, Rho‐kinase inhibitor, and vasodilator	Preclinical
Rho/ROCK	/	Fibrogenesis and differentiation	Heparin	PK/toxicity (DB01109)^h	Repurpose	Thrombosis (IV, 1997), inflammation (IV, 2008), anticoagulation (IV, 2009), Cancer (IV, 2009), IVF‐ET failure, and thrombophilia (IV, 2009)	Nonhormone, anti‐inflammatory agent	Preclinical
Antiangiogenesis agents
Multikinase	VEGFR, PDGFR	Apoptosis and angiogenesis	Sunitinib (SU11248)	PK/toxicity (DB01268)^h	Repurpose	Carcinoma, renal cell (IV, 2008), gastrointestinal stromal tumors (IV, 2008)	Nonhormone, multikinase inhibitor	Preclinical
Multikinase	VEGFR‐2, FGFR‐1 and PDGFR‐β	Angiogenesis	SU6668	PK/toxicity ¹²¹	Repurpose	Hepatocellular carcinoma (II, 2003)	Nonhormone, multikinase inhibitor	Preclinical
VEGF/VEGFR	VEGFR2	Angiogenesis	SU5416	PK/toxicity ¹²⁴	Repurpose	Melanoma (II, 2001), malignant mesothelioma (II, 2000), gastrointestinal stromal tumour, sarcoma (II, 2000)	Nonhormone, VEGFR inhibitor‎	Preclinical
VEGF/VEGFR	VEGF	Angiogenesis and proliferation	Pazopanib (P), sunitinib (SU) and sorafenib (SO)	(P) PK(DB06589)^h, others as mentioned	(P) repurpose, others as mentioned	(P) Cancer (IV, 2010), ovarian cancer (III, 2009), carcinoma, renal cell (II, 2006) others as mentioned	(P) Nonhormone, multikinase inhibitor, others as mentioned	Preclinical
VEGFC mediated c‐JUN, IFN‐γ, CXCL3, and MMP‐9 pathway	VEGFC/VEGFR2	Proliferation and angiogenesis	EGCG	PK ⁶⁷ /toxicity ⁶⁸	Repurpose	Multiple sclerosis (III, 2009), cervical cancer (II, 2005), prostate cancer (II, 2004)	Natural product, catechin	Phase 2
VEGF	VEGF	Proliferation, angiogenesis and oxidative stress	ProEGCG	No information,	New	NA	Natural product, prodrug	Preclinical
NF‐κB/TNF‐α/VEGF	NF‐κB	Angiogenesis	Pyrrolidine dithiocarbamate	PK/toxicity ¹³¹	New	NA	Nonhormone, metal chelator	Preclinical
VEGFC and VEGFR2	VEGFC and VEGFR2	Angiogenesis	PTX	PK/toxicity (DB00806)^h	Repurpose	Hemodialysis (IV, 2006), intermittent claudication (since 1982)	Nonhormone, hemorheological agent	Phase 3
VEGF/VEGFR2	Dopamine receptor 2	Angiogenesis and inflammatory	Quinagolide	PK/toxicity (DB09097)^h	Repurpose	Hyperprolactinaemia (since 1994) ¹³⁴	Nonhormone, dopamine agonist	Phase 4
Antioxidative stress agents
Radical scavenging activity/ERK	ROS	Oxidative stress and proliferation	NAC	PK/toxicity (DB06151)^h	Repurpose	Cystic fibrosis (II, 2008), multiple sclerosis (II, 2004), pulmonary fibrosis (III, 2000),	Nonhormone, antidote	Preclinical
Regulation of antioxidant enzymes	ROS	Oxidative stress	Resveratrol	PK/toxicity (drugs.com/resveratrol.)ⁱ	Repurpose	Inflammation in type 2 diabetic patients (III, 2013), anti‐inflammatory and antioxidant effects (III, 2011)	Natural product, phytoalexin	Phase 4
Regulation of antioxidant enzymes	ROS	Oxidative stress	Caffeic Acid	PK ¹³⁹	Repurpose	Immune thrombocytopenia (III, 2012)	Natural product, phenolic acid	Preclinical
Radical scavenging activity	ROS, MMP, VEGF	Oxidative stress, angiogenesis, and inflammation	Melatonin	PK/toxicity (DB01065)	Repurpose	Insomnia (IV, 2007), chemotherapy‐induced toxicity (III, 2007), prevention of lung cancer (III, 2007)	Hormone, miscellaneous anxiolytics, sedatives, and hypnotics	Phase 2
Anti‐inflammation agents
Cytokines	/	Proliferation, invasion and inflammation	NAC	PK/toxicity (DB06151)^h	Repurpose	Pulmonary fibrosis (III, 2000), cystic fibrosis (II, 2008), multiple sclerosis (II, 2004)	Nonhormone, antidote	Preclinical
Cytokines	/	Proliferation and inflammation	Crocin	PK ¹⁴⁵ /toxicity ¹⁴⁶	Repurpose	Metabolic syndrome (IV, 2010)	Natural product, diterpenoid	Preclinical
Cytokines	/	Inflammation	Metformin	PK/toxicity (DB00331)^h	Repurpose	PCOS (IV, 2003), type 2 diabetes (IV, 2000)	Nonhormone, antidiabetics and biguanides	Preclinical
Cytokines	/	Angiogenesis and inflammation	Resveratrol	PK/toxicity (drugs.com/resveratrol.)ⁱ	Repurpose	Inflammation in type 2 diabetic patients (III, 2013), anti‐inflammatory and antioxidant effects (III, 2011)	Natural product, phytoalexin	Phase 4
TNFα‐mediated cytokines	SIRT1	Inflammation	Resveratrol	PK/toxicity (drugs.com/resveratrol.)	Repurpose	Inflammation in type 2 diabetic patients (III, 2013), anti‐inflammatory and antioxidant effects (III, 2011)	Natural product, phytoalexin	Phase 4
Cytokines	MIF	Angiogenesis and inflammation	ISO‐1	No information	New	NA	Nonhormone, MIF inhibitor	Preclinical
E₂/ER	P450AROM	Inflammation	Puerarin	PK ⁹²	Repurpose	Alcohol abuse (II, 2009)	Natural product, isoflavonoid	Preclinical
MAPK, Wnt pathway	/	Proliferation, angiogenesis, and inflammation	Niclosamide	PK/toxicity (DB06803)^h	Repurpose	Anthelmintic (since 1982)	Nonhormone, anthelmintic agent	Preclinical
IκKα/β, NF‐κB, STAT3, and JNK	Chemokine and cytokines	Angiogenesis and inflammation	Curcumin	PK/toxicity (DB11672)^h	Repurpose	Inflammation in endometrial carcinoma (II, 2013), irritable bowel syndrome (IV, 2008)	Natural product, curcuminoid	Recruiting
NK cells cytotoxicity	/	Immune system	Ginsenoside PPD	PK ⁷⁶ /Toxicity1, 77	Repurpose	Endothelial function (II, 2007)	Natural product, steroid glycoside	Preclinical
VEGF/VEGFR, iNOS/NO, COX‐2/PGE₂	VEGF, iNOS, and COX‐2	Angiogenesis and inflammation	Acai	PK/toxicity (drugs.com/acai)ⁱ	Repurpose	Antioxidant (2010, III), prostate cancer (2011, II)	Natural product, anthocyanin	Preclinical

Medication	Study models	Positive control group	Negative control group	Assessments	Efficacy (compared to untreated)^e, ^f, ^g	Size effects or other comments	Reference
Current medication
Indomethacin	Animals (EM mice model)	NA	Vehicle	Lesions assessment	↓~46% in area of all lesions	Stomach upset, headache, drowsiness, dizziness, and so forth. ¹	[60]
Celecoxib	Cells (Primary human endometriotic stromal cells)	NA	Vehicle	Proliferation and apoptosis assays, IHC, Western blot, ELISA	↓~60% in proliferation, ~50% VEGF and ~70% PGE₂, ↑ ~3.25‐fold in apoptosis and ~2‐fold COX‐2 expression with 100 µM of celecoxib	Stomach upset, headache, drowsiness, dizziness, and so forth. ¹	[53]
GnRH agonist	Cells (primary human endometriotic stromal cells)	NA	Untreated	Western blot, EMA	↓~80% TNF‐α mediated IL‐8 level	Hypoestrogenic31, 32	[31]
Progesterone or dienogest or danazol	Cells (primary human endometriotic stromal cells)	NA	Untreated	EMA, ELISA, Northern blot analysis	↓~40% in TNF‐α mediated IL‐8 level	Hypoestrogenic31, 32	[50]
Leuprolide acetate	Cells (primary human eutopic epithelial endometriotic cells)	NA	Basal conditions	Apoptosis assay, ELISA	↑1.74‐fold in apoptosis level, ↓62.5% in IL‐8 level, and ↓52.6% in VEGF level	Hypoestrogenic31, 32	[52]
Dienogest	Cells (primary human endometriotic stromal cells)	AKT inhibitor VIII and U0126	Untreated	Western blot, TEM, IF, autophagy, and apoptosis assays	↑~1.5‐fold of LC3‐II and SQSTM1 expression, ~25% in autophagy level, ↓~40% in p‐Akt and p‐ERK	Hypoestrogenic31, 32	[61]
Antiproliferation and proapoptotic agents
BAY11‐7085	Cells (primary human endometriotic and endometrial stromal cells)	NA	Untreated	MTT, ELISA, apoptosis assay, flow cytometry, Western blot	↓66.1% cell viability and ↑725.1% in apoptosis ability with 10 µM of BAY11‐7085 in ECSCs	No information	[62]
Melatonin	Animals (EM rat model)	Vehicle	NA	H&E, Western blot, RT‐PCR, EMSA, Tunel assay	↓~80% secreted proMMP‐3 and ↓ ~80% synthesized proMMP‐3 on 35th day	No side effects reported	[63]
Chloroindazole	Cells (primary human endometriotic stromal cell) and animals (EM mice model)	NA	Vehicle	Lesions assessment, WST‐1 assay, Tunel assay, qRT‐PCR, LC‐MS	↓~88% in lesions weight, ↓~90% in Ki67 and p65 cells, ↓~88% in IL‐6 cells, in the therapeutic model, ↓~60% cell viability	No adverse effects on the reproductive tract or disturb estrous cycling or fertility	[64]
Oxabicycloheptene sulfonate	Cells (primary human endometriotic stromal cell) and animals (EM mice model)	NA	Vehicle	Lesions assessment, WST‐1 assay, Tunel assay, qRT‐PCR, LC‐MS	↓~78% in lesions weight, ↓~85% in Ki67 and p65 cells, ↓~78% in IL‐6 cells, in the therapeutic model, ↓~60% cell viability	No adverse effects on the reproductive tract or disturb estrous cycling or fertility	[64]
Resveratrol	Cell line (Ishikawa cells) and animals (EM xenograft model)	Progesterone	Vehicle	Alkaline phosphatase assay, IHC, RT‐PCR	↓~50% ESR1 and ~60% Ki67 expression in epithelium in high dose	Mild, mainly related to headache and somnolence ⁶⁵	[66]
EGCG	Cells (primary human endometrial stromal and glandular cells), and animals (EM Syrian golden hamsters model)	NA	DMSO in vehicle (animal) and vehicles (cells)	Lesions and microvessel assessment, WST‐1 assay, Western blot, Intravital fluorescence microscopy, H&E	↓~28.5% of E₂ induced activation and ~33.3% E₂ induced VEGF in EGC; ↓~38.5% endometriotic lesions regression; ↓50% of volumetric blood flow in endometriotic lesions on Day 14	Well tolerated, only mild headache and fatigue ⁶⁹	[70]
Tunicamycin	Cells (primary human endometriotic and endometrial stromal cells)	TRAIL	Vehicle	qRT‐PCR, Flow cytometry	↑59.1% in apoptosis (−TRAIL) ↑1.35‐fold in apoptosis (+TRAIL) in women with EM	Major neurotoxicity and death in animals ⁷²	[73]
Verteporfin	Cells (primary human endometriotic stromal cells) and animals (EM mice model)	NA	Vehicle	Western blot, IHC, ChIP assay, MTS assay, GSEA, Lesions assessment,	↓Proliferation in a dose‐dependent manner, ↓~50% in migration and tube formation, ↓~57% in lesions weight	Visual disturbances ⁷⁴	[75]
Ginsenoside Rg3	Cells (primary human endometriotic stromal cells)	NA	Untreated	CCK8, Western blot, RT‐PCR	↓~40% cells after 72 h with 150 µg/ml Rg3, ↓ TNF‐α induced effect of NF‐κB p65 (~20%), VEGF (~25%) and ↑~25% TNFα induced effect of CASP3	No side effect reported from RCTs ⁷⁸	[79]
Curcumin	Animals (EM mice model)	Celecoxib	PBS	Lesions assessment, H&E, Western blot, AFM, electrophoresis	↓~80% lesions glands, ↓~60% of p65/NF‐κB expression, ↑~6‐fold of Bax/bcl2 ratio on Day15	Safe and well‐tolerated even at high dose ⁸⁰	[81]
Genistein	Animals (EM mice model)	Dienogest and Leuprolide acetate	Untreated	Lesions assessment, IHC	↓4% of TGF‐β and 4.5% NF‐κB, 3.4% Bcl‐2, 1.35% COX2, 2% PGE, ↑1.35% Bax expression levels with 1.30 mg/day of Genistein	No side effect reported83, 84	[85]
Sorafenib	Cells (primary Human endometriotic stromal cell), and animals (EM mice xenograft model)	NA	Untreated (cell) or placebo (animal)	Lesions assessment, crystal violet assay, Western Blot, H&E	↓99.7% decreased in ectopic stromal cell, ↓64% in pERK–ERK ratio, ~33.3% in pVEGFR‐VEGFR ratio, ~35% implants size	Weight loss, skin, and gastrointestinal toxicities ⁸⁶	[87]
Vemurafenib	Cells (primary human stromal/epithelial; endometriotic/endometrial cells) and animals (EM mice xenograft model)	NA	vehicle (1% DMSO in media)	Western blot, IHC, lesions assessment, viability, apoptosis, and crystal violet assay assays	↓viability (69%, 66.7%), ↓optic density of pERK/ERK (62%, 61%), BRAF/B‐actin (61%, 66%) in stromal, epithelial cells, ↓ 37% implants size	Arthralgias, rash, and hyperkeratosis ⁸⁸	[89]
U0126	Cells (primary human endometriotic and endometrial stromal cells)	Progestin (R5020)	DMSO	Immunoblotting, qRT‐PCR, Viability assay, IHC	↑~10% PRAB, ↓~20% viability in OSIS with 10uM of U0126	No information	[91]
Puerarin	Cells (primary human endometriotic stromal cells)	U0126	Vehicle	Binding assay, Western Blot, CCK‐8, qRT‐PCR, and phosphate kinase arrays	Relative binding affinity of 32.2% of ERs and puerarin complex, ↓~30% proliferation, and ERK related proteins: ↓~46% cyclin D1, ↓~73% COX‐2, and ↓~46% cyp19	Can be used for long periods without severe side effects	[93]
PGE₂ inhibitors	Cell line (12Z and 22B), Cells (primary human endometriotic and endometrial stromal cells)	NA	Untreated	Western blot, IP, IF, TUNEL, RT‐PCR, IHC	↑Apoptosis in 12Z (~8‐fold) and 22B (~7‐fold), ↓ p‐EGFR/EGFR level in 12Z (~85%) and 22B (~63%), ↓ pERK/ERK level in 12Z (~50%) and 22B (~15%), ↓pAkt/Akt level in 12Z (~85%) and 22B (~72%), ↓B‐cate/B‐actin level in 12Z (~67%) and 22B (~43%),	GI upset, edema, and skin rash ⁹⁴	[95]
WIN 55212‐2	Cells (primary human stromal/epithelial; endometriotic/endometrial cells) and animals (EM mice xenograft model)	NA	PBS	Proliferation and viability assays, Western blot, lesions assessment	↓65% Akt level in endometriotic stromal cell and 50% that in endometrial stromal cell, ↓43% in lesions volume	Dizziness, drowsiness, sedation, dry mouth and cognitive impairment ⁹⁷	[98]
MK2206	Cells (primary human endometriotic and endometrial stromal cells) and animals (EM xenograft mice model)	Progestin (R5020)	DMSO in vehicle (cell) and PBS (animal)	Lesions assessment, Western blot, qRT‐PCR, viability assay, IHC	↑~20% PRA and 30% PRAB, ↓~30% viability in OSIS with 10 µM of MK2206, ↓ ~20% tumor volume	No information	[91]
Propofol	Cell line (CRL‐7566)	NA	0.2% DMSO in vehicle	MTT, Flow cytometry, RT‐qPCR, Western blot	↑~35% in apoptosis level with 10 µg/ml propofol, ↑ FOXO1, FOXO3, Bim, p21, p53, CASP3 expression levels in a dose‐dependent manner	Hemodynamic instability, pain on injection, dystonic movements, hypertriglyceridemia, pancreatitis, allergic reactions ⁹⁹	[100]
Dichloroacetate	Cells (primary human peritoneal mesothelial cells), cell line (SHT290), animals (EM mice model)	NA	Vehicle (water)	ECAR and OCR measurement, Enzymatic colorimetric kit, Lesions assessment	↓~40% TGF‐β1–stimulated HPMC lactate secretion, ~25% cell proliferation, ↑ ~3‐fold PDH activity, ↓~20% lactate concentrations in PF, and ~50% lesions size	Peripheral neuropathy	[46]
Autophagy modulators
MK2206 and chloroquine	Cells (primary human stromal/epithelial; endometriotic/endometrial cells) and animals (EM mice xenograft model)	NA	Vehicle	MTS, flow cytometry, transfection, Western Blot, IF, clonogenic assay, IHC	↓>80% proliferation in both cell growth and regrowth model in all cells and, >90% colony formation in both DES and EES, ↓>80% lesions volume, ↑>50% apoptosis in mice	Chloroquine alone might result in gastrointestinal symptoms but no information of adverse effects with combination treatment	[102]
Ginsenoside PPD	Cells (primary human endometriotic and endometrial stromal cells) and animals (EM mice model)	Esculentoside A	0.1% DMSO in vehicle	CCK8, flow cytometry, RT ² profiler™ PCR, Western blot, IHC, IF	>3‐fold difference in autophagy‐related genes ATG2, ATG3, and ATG5, ESR1, SQSTM1, and TGF‐B1, ↓~90% lesions weight and ~85% of lesions numbers with high dose PPD	Safe, low doses had no influence on growth of nESCs or the eutopic endometrium	[103]
MIS	Cell line (CRL‐7566)	NA	PBS	MTT, FACS analysis, flow cytometric analysis, Western blot	↓50% viability, ↑1.8‐fold proptosis with 10 µg/ml MIS	No information	[104]
Antimigration, anti‐invasion, and antifibrosis agents
C‐82	Cells (primary human endometriotic and endometrial stromal cells)	NA	Vehicle	IHC, MTT, Western blot, ELISA, qRT‐PCR, scratch assay	↓51.8% cell viability, 91.9% cell proliferation, ↑200% apoptosis and 234.2% CASP3/7, ↓54% cell migration, all with 20 µM of C‐82	Mild, e.g reaction at the injection site, nausea, and constipation	[106]
ICG‐001	Cells (primary human endometriotic and endometrial stromal cells) and animals (EM mice model)	NA	Vehicle	IHC, MTT, Western blot, ELISA, qRT‐PCR, scratch assay, lesions assessment	↓20.8% cell viability, 86.1% cell proliferation, ↑56.4% apoptosis, 128.9% CASP3/7, ↓64%cell migration, all with 20 µM of ICG‐001, ↓~87.5% number of lesions	High dose was required for preclinical study and might not be comparable to clinical study	[106]
PKF115‐584	Cells (primary human stromal/epithelial; endometriotic/endometrial cells)	NA	Vehicle	qRT‐PCR, proliferation and migration assay, Western blot	↓73% invasion in endometriotic epithelial cells and 75% invasion, 85% MMP‐9 in stromal cells	Wnt/B‐catenin is needed for stem cell maintenance and tissue homeostasis ¹⁰⁷	[108]
Metformin	Cells (primary human endometriotic and endometrial stromal cells, endometrial epithelial cell)	NA	Untreated	MTT, Western blot	↓36.9% growth effects on epithelial cells by stromal factors, ↓~50% Wnt2 expression and secretion	Nausea and vomiting, diarrhea, abdominal pain ¹⁰⁹	[48]
PKF115‐584/CGP049090	Cells (primary human endometriotic and endometrial stromal cells)	NA	Vehicle	qRT‐PCR, MTS, migration assay, ICC, collagen gel contraction assay	↓>70% mRNA levels of αSMA, COL‐I, FN, CTGF in endometriotic stromal cell, collagen gel contraction	Wnt/B‐catenin is needed for stem cell maintenance and tissue homeostasis ¹⁰⁷	[110, 111]
EGCG	Cells (primary human endometriotic and endometrial stromal cells) and animals (EM mice model)	NAC	Vehicle	qRT‐PCR, MTS, migration and invasion assays, Collagen gel contraction assay, ICC, Western blot, H&E	↓>90% mRNA levels of αSMA, COL‐I, FN, CTGF in endometriotic stromal cell, ↓ > 90% migrated and invasive cells	Well tolerated, only mild headache and fatigue ⁶⁹	[110]
Genistein	Animals (EM mice model) and In silico	NA	Untreated	Lesions assessment, ELISA, docking	↑21.91 kJ/mol and 63.14 kJ/mol of NF‐κB to MMP‐2/‐9 binding energy, ↓~50% MMP‐2, ~30% MMP‐9 expression level with 100 mg/day genistein	No side effect reported83, 84	[112]
Fasudil	Cells (Primary human endometriotic stromal cells)	NA	Untreated	Cell viability assay, ELISA, flow cytometry, Collagen gel contraction assay, Western blot, Morphology assessment	↓43.7% proliferation, ~50% cell density, ~25% Bcl‐2, ~50% Bcl‐xl, αSMA, ROCKI, and ROCKII protein expressions, ~↑2‐fold apoptosis, 50% contractility, all with 100 µM Fasudil	Systemic vasodilation and hypotension ¹¹⁴	[115]
Heparin	Cells (Primary human endometriotic stromal cells)	NA	Untreated	Morphology assessment, collagen gel contraction assay, Western blot	↓55.7% gel contraction with 100 mg/ml heparin sodium solution, ↓ αSMA, RhoA, ROCKI, and ROCKII expressions levels	Thrombocytopenia ¹¹⁶	[117]
Antiangiogenesis agents
Sunitinib (SU11248)	Animals (EM rat model)	NA	Saline	Lesions assessment, H&E, and Tunel assay	↓78.8% in cross‐sectional area of the cyst, and 50% complete cyst disappearance in animal	fatigue, diarrhea, skin discoloration, and nausea ¹¹⁸	[119, 120]
SU6668	Animals (EM golden hamster model)	NA	DMSO	Lesions assessment, H&E, IHC	↓~30% vascularized area of endometrial grafts, ↓~50% microvessel density, ↓~25% size of endometrial grafts	Fatigue, nausea, vomiting, diarrhea, pain, flu‐like complaints, anorexia, change of taste ¹²²	[123]
SU5416	Animals (EM golden hamster model)	NA	DMSO	Lesions assessment, H&E, IHC	↓~20% microvessel density, ↓~5% size of endometrial grafts	Headache, pain at injection site ¹²⁵	[123, 126]
Pazopanib (P), sunitinib (SU) and sorafenib (SO)	Animals (EM rat model)	NA	Saline	Lesions assessment, H&E, IHC	↓~16% (SU), ~45% (P) in EM score; ↓~83%(SO), ~66% (SU), ~50% (P) in VEGF; ↓~56% (SU), ~40% (P) in CD117	Adverse effects on reproductive functions in animal models, including ovulation inhibition, embryotoxicity ¹²⁷	[128]
EGCG	Cells (human microvascular endothelial cells), and animals (EM mice xenograft model)	Vitamin E	Saline	Lesions and microvessel imaging, microarray, qRT‐PCR, Western blot, IHC	↓85% size and total vessel area of lesions with human endometrium tissue, ↓48% VEGFC mRNA, ↓~50% VEGFC expression level	Well tolerated, only mild headache and fatigue ⁶⁹	[70, 129]
ProEGCG	Animals (EM mice xenograft model)	Vitamin E	PBS	Lesions and Microvessel imaging, H&E, Tunel assay, ELISA, ORAC assay	↓>90% in lesions weight and size, ↓>70% in VEGF concentration, and ↑>4‐fold ORAC capacity in plasma and lesions during intervention	No sign of side effects	[130]
Pyrrolidine dithiocarbamate	Cells (primary human endometriotic and endometrial stromal cells)	NA	NA	EMSA, RT‐PCR, and Western blot	↓63.5% in TNFα–induced NF‐κB‐DNA binding activity, 53.9% CD44s, 55.2% MMP‐9, 68.5% VEGF expression in endometriotic stromal cells with 50 umol/L PD	No information	[132]
PTX	Animals (EM Wistar rats model)	NA	0.9% NaCl in vehicle	Lesions assessment, H&E, IHC	↓37.9% mean implant volume per animal, ↓47% VEGFC, and 40.1% Flk‐1 in glandular cells	No sign of side effects	[133]
Quinagolide	Human (hyperprolactinemic patients with EM)	NA	NA	Lesions morphology assessment, IHC, IF, and superarray	↓69.5% lesions size and 35% of lesions vanished completely, ↓VEGF (5.8‐fold), CCL2 (6.1‐fold), ↑CCL10 (6.8‐fold)	Dizziness, nausea, and vomiting	[135]
Antioxidative stress agents
NAC	Cells (primary human stromal/epithelial; endometriotic/endometrial cells), animals (EM mice xenograft model)	Danazol and Mifepristone	PBS or sesame oil	UV spectroscopy, viability assays, H&E, Western blot, antioxidant enzyme activities	↓40%–60% H₂O₂ concentrations and 30%–60% proliferation in mice, ↓88% ratio pERK/ERK in human OSIS	High amount cause nausea, vomiting ¹³⁶	[137]
Resveratrol	Animals (EM rat model)	NA	Vehicle	Lesions assessment, H&E, PCNA‐IHC, antioxidant enzyme activities	↓41.5% of implants, ↑~50% (serum) and ↑ ~2‐fold (tissues) in SOD and GSH‐px activities, ↓46% (serum) and 77% (tissue) MDA, all with high dose resveratrol	Mild, mainly related to headache and somnolence ⁶⁵	[138]
Caffeic Acid	Cells (primary human endometriotic and endometrial stromal cells)	NA	Untreated	IHC, MTT, antioxidant activity assays	↓48.8% MDA ↑90.7% GSH, 56% CAT, 81% GPx, 59.5% GR	Excessive consumption can have insomnia ¹⁴⁰	[141]
Melatonin	Animals (EM rat model)	Vehicle	NA	Antioxidant activity assays, H&E, IHC	↓68.1% weight of implants, ↓ 66.8% in volume weight and ↓ 75.2% histologic score, ↓ 24% MDA, ↓45.6% CAT and ↑ 1.77‐fold SOD activities level, ↓ 61% VEGF ↓ 70% MMP‐9	No negative effect on fertility	[142, 143]
Anti‐inflammation agents
NAC	Animals (EM mice model)	NA	Vehicle	Lesions assessment, IHC, qRT‐PCR	↓60% lesions, ↓54% Ki67, ~50% COX2, >60% MMP‐9 levels	High amount cause nausea, vomiting ¹³⁶	[144]
Crocin	Animals (EM mice model), and cell line (HUVEC and THP‐1)	NA	Untreated and saline	Lesions assessment, IHC, qRT‐PCR, ELISA, FC	↓~44% lesion size and ~64% of lesion weight, ~80% of VEGF and ~60% PCNA mRNA levels, ↓>50% of INF‐γ, TNF‐α, VEGF, and IL‐6 in serum	Mild effects like headache, insomnia, nausea, and dyspnea ¹⁴⁷	[148]
Metformin	Human (Stage1–2 EM patients)	NA	Placebo	ELISA	↓~35% IL6, ~33% IL‐8 and ~38% VEGF	Nausea and vomiting, diarrhea, abdominal pain ¹⁰⁹	[149]
Resveratrol	Animals (EM rat model)	NA	Vehicle	Lesions assessment, ELIZA, H&E, IHC	↓84.8% of implants volume, ↓VEGF level in Peritoneal fluid (54.8%), plasma (55.5%) and lesions (80.5%), ↓MCP‐1 in peritoneal fluid (48.3%)	Mild, mainly related to headache and somnolence ⁶⁵	[150]
Resveratrol	Cells (primary human endometriotic and endometrial stromal cells)	NA	Untreated	qRT‐PCR, CCK‐8, IHC, ELIZA	↓>60% TNFα induced IL‐8 mRNA expression and concentrations in ESC	Mild, mainly related to headache and somnolence ⁶⁵	[151]
ISO‐1	Animals (EM mice model)	NA	5% DMSO in vehicle	Lesions assessment, qRT‐PCR, Western blot	↓~70% in implant size, ~60% Flk‐1 expression, ~50% MIF activity	No information	[151]
Puerarin	Animals (EM rat model)	Raloxifene hydrochloride	Sodium carboxymethyl cellulose	Lesions and blood assessment, RT‐PCR, IHC	↓35.3% weight, ↓21.6% E2, 69.4% P450AROM, 41.5% COX‐2, 59.2%, 17β‐hsd‐1m, and ↑2.3‐fold 17β‐hsd‐2m mRNA of ectopic endometrium with M‐SI group	Can be used for long periods without severe side effects ⁹³	[152]
Niclosamide	Animals (EM mice model)	NA	Vehicle	Lesions assessment, IHC, IF, TUNEL, qPCR, GSEA	↓63.6% implant weight, 78.1% growth, 38.8% epithelial cell proliferation with 200 mg/kg niclosamid, ↓MAPK, Wnt, inflammation signaling‐related genes mRNA expression levels	Mild nausea and abdominal pain ¹⁵³	[154]
Curcumin	Cells (primary human endometriotic and endometrial stromal cells)	NA	0.1% DMSO in vehicle	Morphology assessment, Western blot, magnetic bead‐based assays	↑apoptosis, ↓phosphorylated form of IKKα/β, NF‐κB, STAT3, and JNK signaling, ↓10–15‐fold IL6, IL‐8, IP10, G‐CSF, MCP‐1 and RANTES, ↑ IL10, IL12, all in a dose‐dependent manner	Safe and well‐tolerated even at high dose ⁸⁰	[155]
Ginsenoside PPD	Cells (primary human endometriotic and endometrial stromal cells) and Animals (EM mice model)	Esculentoside A	0.1% DMSO in vehicle	CCK8, Flow cytometry, RT ² profiler™ PCR, Western blot, IHC, IF	↓~33.3% Bcl‐2, ~15% Bcl‐xL, and ~17% Ki‐67, ↑~28% CD82 in NK cells, ↓~67% E₂ induced lesion, and ~70% E₂ induced lesions weight	Safe, low doses had no influence on growth of nESCs or the eutopic endometrium	[103]
Acai	Cell line (J774.G8) and animals (Sprague‐Dawley rats)	NA	Vehicle	Lesions assessment, H&E, IHC, RT‐qPCR, ELIZA, flow cytometry, MTT	↓~92% lesions, ~33.3% VEGF conc., ~80% MMP‐9, 57% PGE2, ~50% viability with 40 µg/ml acai for 72 h	No information	[156]

Abbreviations: 17β‐hsd, 17β‐hydroxysteroid dehydrogenase; ‐SMA, ‐smooth muscle actin; AFM, atomic force microscopy; AKT, protein kinase B; P450AROM, aromatase; ASK1, apoptosis signal‐regulating kinase 1; ATF4, activating transcription factor 4; ATG, autophagy‐related protein; BRAF, serine/threonine‐protein kinase B‐Raf; CASP, caspases; CAT, catalase; CB, cannabinoid receptor; CCK8, cell counting kit‐8; CDK, cyclin‐dependent kinases; CHOP, CCAAT/enhancer‐binding protein homologous 10 protein; COL, collagen; COX, cyclooxygenase; CTGF, connective tissue growth factor; CXCL3, chemokine ligand 3; CYPs, cytochromes P450; DMSO, dimethyl sulfoxide; DVT, deep vein thrombosis; E₂, estrogen; ECAR, extracellular acidification rate; EGCG, epigallocatechin gallate; EGFR, epidermal growth factor receptor; eIF2α, eukaryotic initiation factor 2 alpha; ELISA, enzyme‐linked immunosorbent assay; EM, endometriosis; ECSCs, endometriotic cyst stromal cells; EMSA, electrophoretic mobility shift assay; ER, estrogen receptor; ER stress, endoplasmic reticulum stress; ERK, extracellular signal‐regulated kinase; ESR1, estrogen receptor 1; FGFR, fibroblast growth factor receptors; Flk‐1, vascular endothelial growth factor receptor 2; FN, fibronectin; GnRH, gonadotropin‐releasing hormone; GI, gastrointestinal; GSHPx, glutathione peroxidase; GR, glutathione reductase; GRP, G protein‐coupled receptor; GSH, glutathione; H&E, haemotoxylin and eosin; ICC, immunocytochemistry; IF, immunofluorescence; IHC, immunohistochemistry; IFN‐γ, interferon‐γ; IL, interleukin; iNOS, inducible nitric oxide synthase; IRE1, inositol‐requiring enzyme 1; IκB, stimulate inhibitor of NF‐κB; IκK, IκB kinase; JNK, c‐Jun N‐terminal kinase; LATS1, large tumor suppressor kinase 1; LC, lapidated microtubule‐associated proteins 1 A/1B light chain; MAPK, mitogen‐activated protein kinase; MDA, malondialdehyde; MEK, ERK kinase; MIF, macrophage migration inhibitory factor; MIS, Mullerian‐inhibiting substance; MMP, matrix metallopeptidases; mTOR, mammalian target of rapamycin; mRNA, messenger RNA; MTT/MTS, cell proliferation assay; NAC, N‐acetyl cysteine; nESCs, normal endometrial stromal cells; NF‐κB, nuclear factor κB; NK cells, natural killer cells; NO, nitrogen oxide; OCR, oxygen consumption rate; ORAC, oxygen radical absorbance capacity; OSIS, endometriotic stromal cells; PCNA, proliferating cell nuclear antigen; PDGF, platelet‐derived growth factor; PDGFR, platelet‐derived growth factor receptor; PDH, pyruvate dehydrogenase kinase; PERK, endoplasmic reticulum kinase; PGE2, prostaglandin E2; PI3K, phosphoinositide 3‐kinases; PK, pharmacokinetics; PPAR, peroxisome proliferator‐activated receptor; PPD, protopanaxadiol; PR, progesterone receptor; ProEGCG, prodrug of EGCG; PTX, pentoxifylline; RAF, RAF proto‐oncogene serine/threonine‐protein kinase; RT‐qPCR, real‐time reverse‐transcription polymerase chain reaction; Rho, Ras homolog family; ROCK, Rho‐associated coiled‐coil kinase; ROS, reactive oxidative stress; SIRT1, sirtuin 1; SOD, superoxide dismutase; STAT, signal transducer and activator of transcription; SQSTM1, sequestosome 1; TCF, T‐cell factor; TCM, traditional Chinese medicine; TGF, transforming growth factors; TNF, tumor necrosis factor; TRAIL, TNF‐related apoptosis inducing ligand; TRAF2, TNF receptor‐associated factor 2; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; Wnt, wingless‐type mouse mammary tumor virus integration site family; WST‐1, cell proliferation assay; YAP, Hippo/Yes‐associated protein.

^{^a}

Pk and toxicity profile of drugs can be found on The Drugs.com Database, drugs.com, or on DrugBank Online, go.drugbank.com, or otherwise as stated.

^{^b}

A new drug is defined as a chemical that has not been studied in clinical trials for other diseases before EM and a repurposed drug is defined as a chemical that has been studied in clinical trials for other diseases before EM.

^{^c}

Representative clinical indications of drugs shows the original purpose before it was studied on EM. Information was taken from US National Library of Medicine, ClinicalTrials.gov, or otherwise as stated.

^{^d}

Data were extracted from The Drugs.com Database, drugs.com or DrugBank Online, go.drugbank.com.

^{^e}

Representative parameters were selected to show efficacy of drugs under corresponding pathophysiology.

^{^f}

Parameters of treated groups with a statistical difference of p < 0.05, compared to controls groups.

^{^g}

Data were extracted from tables or read from graphs.

^{^h}

Drug accession number is the ID of each drug entry on Drug bank.

^ⁱ

Drug entry on the drug.com can be accessed via the URL.