Asherman_Syndrome

Acquired MONDO:0015299 Pathograph 36 Show in embeddings browser uterine disease endometrium disease

Asherman syndrome is symptomatic intrauterine or endocervical adhesion disease. Endometrial injury, commonly after pregnancy-related uterine instrumentation and occasionally infection or other uterine procedures, can heal with fibrous tissue and bridging adhesions. Menstrual disturbance, cyclic pain, infertility or pregnancy loss may follow. Residual endometrium and regenerative capacity vary; complete stem-cell depletion is not required or demonstrated in every case. Hysteroscopy defines the cavity lesion and enables adhesiolysis, but recurrence and impaired reproductive outcomes may persist.

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2
Definitions
18
Pathophys.
9
Phenotypes
4
Hypotheses
4
Gaps
36
Pathograph
9
Medical Actions
3
Differentials
1
Trials
7
Models
17
References
1
Deep Research
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Classifications

Harrison's Part
ENDOCRINOLOGY METABOLISM
📘

Definitions

2
Symptomatic intrauterine adhesion disease
Intrauterine or endocervical adhesions accompanied by attributable menstrual disturbance, pain or reproductive dysfunction constitute the symptomatic syndrome; every symptom is not required.
DIAGNOSTIC_CRITERIA
Inclusion criteria
  • Intrauterine adhesions established by cavity assessment
  • Attributable pain, menstrual disturbance or subfertility in any combination
Show evidence (1 reference)
PMID:28603474 SUPPORT REVIEW SYNTHESIS Human Clinical
"The terms “Asherman syndrome” and IUAs are often used interchangeably, although the syndrome requires the constellation of signs and symptoms (in this case, pain, menstrual disturbance, and subfertility in any combination) related to the presence of IUAs"
Guideline distinction between an anatomical finding and the symptomatic syndrome.
Hysteroscopic severity classification
Document adhesion extent, density, location and residual cavity/endometrium. AFS also incorporates menstrual features; March, ESGE and other schemes use different criteria. Categories describe severity rather than inevitable sequential stages.
OTHER
Show evidence (2 references)
PMID:28603474 SUPPORT REVIEW SYNTHESIS Other
"Intrauterine adhesions should be classified as prognosis is correlated with severity of adhesions. Level B."
The guideline supports recording severity.
PMID:28603474 SUPPORT REVIEW SYNTHESIS Other
"Consequently, it is currently not possible to endorse any specific system. Level C."
Classification systems remain heterogeneous.
Notes: No single system was endorsed as superior in the AAGL/ESGE guideline; outcome associations do not constitute a validated individual live-birth prediction tool.
◈

Mechanistic Hypotheses

4
Altered epithelial differentiation within a dysfunctional niche
niche_dysfunction EMERGING
Evidence balance 1 support
Human transcriptional and inferred communication differences suggest altered epithelial differentiation. Cross-sectional composition, HRT exposure and control-dataset differences do not establish WNT or NOTCH as necessary causal routes.
Pathograph links
Reduced WNT Communication Signature -> Reduced Receptive Endometrial Surface INDIRECT UNKNOWN INTERMEDIATES Altered WNT communication may contribute to impaired epithelial differentiation and receptivity; composition, hormone exposure and causality are unresolved.
Reduced NOTCH Communication Signature -> Reduced Receptive Endometrial Surface INDIRECT UNKNOWN INTERMEDIATES A differentiation-related contribution is proposed; no intervention isolates NOTCH as the cause of human infertility.
Show evidence (1 reference)
PMID:37735465 SUPPORT PRIMARY RESULT Human Clinical
"Our endometrial atlas highlights the loss of the endometrial epithelium, alterations to epithelial differentiation signaling pathways such as Wnt and Notch, and the appearance of characteristic epithelium expressing secretory leukocyte protease inhibitor during the window of implantation."
Human recovered-cell and transcriptional observations; cell proportions are not stereological tissue-volume measurements.
DIO2-associated autophagy changes amplify epithelial stress
autophagy_defect_emt EMERGING
Evidence balance 2 support
DIO2 perturbation, phosphorylation readouts and pharmacological interventions support an experimental autophagy-related contribution to partial EMT-like changes. Static human markers are not direct dynamic flux assays, and no complete genetic mediation chain or human treatment benefit is established.
Pathograph links
Reduced Epithelial DIO2 Expression -> Increased ERK Phosphorylation INDIRECT UNKNOWN INTERMEDIATES DIO2 knockdown is associated with increased ERK phosphorylation in culture; the intervening mechanism is unresolved.
Increased ERK Phosphorylation -> Increased MTOR Phosphorylation INDIRECT UNKNOWN INTERMEDIATES MEK-pathway inhibition reduces the MTOR-associated phosphorylation state after DIO2 knockdown, supporting indirect pathway involvement.
Increased MTOR Phosphorylation -> Reduced Epithelial Autophagy INDIRECT UNKNOWN INTERMEDIATES MTOR-associated signaling is proposed to suppress autophagy in this experimental context; no selective ATG genetic epistasis establishes the complete route.
Reduced Epithelial Autophagy -> Epithelial Mesenchymal Marker Shift INDIRECT UNKNOWN INTERMEDIATES Chloroquine and rapamycin oppositely modify EMT-associated markers; drug pleiotropy and non-autophagic effects remain possible.
Show evidence (2 references)
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/ SUPPORT PRIMARY RESULT In Vitro
"In endometrial epithelial cells (EECs), pharmacological inhibition of autophagy by chloroquine (CQ) promoted EEC-EMT, whereas enhanced autophagy by rapamycin extenuated this process."
Pharmacological effects on epithelial/mesenchymal markers; not genetic epistasis or lineage tracing.
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/ SUPPORT PRIMARY RESULT In Vitro
"Importantly, the cytoprotective effect of DIO2 overexpression was lost in the CQ pre-treated EECs"
Pharmacological blockade supports an autophagy-related contribution to the marker phenotype, with drug pleiotropy unresolved.
Ferroptotic epithelial stress promotes stromal fibrosis through transferable signals
ferroptosis_amplification EMERGING
Evidence balance 2 support
Erastin affects epithelial preparations and their supernatant promotes stromal fibrosis, unlike direct stromal exposure. The necessary secreted mediator, pathway specificity and human causal sequence remain unresolved.
Pathograph links
Epithelial Ferroptotic Stress -> Epithelial Mesenchymal Marker Shift INDIRECT UNKNOWN INTERMEDIATES Erastin causes EMT-associated marker changes in epithelial preparations; this does not establish all injury-associated EMT as ferroptosis-dependent.
Epithelial Ferroptotic Stress -> Epithelial Profibrotic Supernatant Activity INDIRECT UNKNOWN INTERMEDIATES Supernatant from erastin-stimulated epithelial cells carries fibrogenic activity; the responsible mediator remains unidentified in the accessible source.
Epithelial Profibrotic Supernatant Activity -> Stromal Fibrogenic Activation INDIRECT UNKNOWN INTERMEDIATES The culture transfer experiment supports stromal response to epithelial supernatant without identifying the necessary secreted factor.
Show evidence (2 references)
PMID:37302615 SUPPORT PRIMARY RESULT In Vitro
"In vitro experiments showed that erastin-induced ferroptosis promoted EMT and fibrosis in endometrial epithelial cells (P < 0.05), but did not lead to pro-fibrotic differentiation in endometrial stromal cells (HESCs)."
Abstract-limited preparation-specific perturbation; epithelial and stromal responses differ.
PMID:37302615 SUPPORT PRIMARY RESULT In Vitro
"Cell co-culture experiments showed that erastin-stimulated epithelial cell supernatants promoted fibrosis in HESCs (P < 0.05)."
Transferable supernatant activity supports epithelial-stromal coupling; the responsible mediator is unresolved in the accessible abstract.
Endothelial marker transitions may contribute to fibrosis
endmt_source EMERGING
Evidence balance 1 support
Rat CD31/alpha-SMA co-localization motivates an endothelial-source hypothesis. It does not quantify lineage conversion or establish that human myofibroblasts arise from endothelium.
Pathograph links
Endothelial Mesenchymal Marker Coexpression -> Excessive Endometrial Matrix Deposition INDIRECT UNKNOWN INTERMEDIATES An endothelial contribution is a model-derived hypothesis based on co-localized markers accompanying fibrosis, not proven lineage-mediated matrix production.
Show evidence (1 reference)
PMID:34996477 SUPPORT PRIMARY RESULT Model Organism
"Immunofluorescence co-localization of CD31 and a-SMA showed that 14 days after moulding, double positive cells for CD31 and a-SMA could be clearly observed in the endometrium."
CD31/alpha-SMA co-localization in the rat injury model; no endothelial lineage tracing quantifies conversion into fibroblasts.
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Discussions and Knowledge Gaps

4
Which injury and niche features determine regeneration versus persistent scarring?
KNOWLEDGE GAP gap_regenerative_capacity
Attached to
pathophysiology#Endometrial Basal Layer Injury pathophysiology#Excessive Endometrial Matrix Deposition
Residual epithelial populations, injury depth, hormonal state, inflammatory context and niche interactions may all matter. Existing evidence does not identify one necessary switch or prove that complete progenitor depletion is required. The contribution of epithelial/stromal plasticity is species- and injury-dependent.
Proposed experiments
Matched longitudinal injury and repair profiling
exp_matched_injury_niche
Compare defined injury depths and hormonal states with serial tissue histology, epithelial coverage and validated lineage tracing in an appropriate model. Match human observational samples by cycle, treatment and sampling location rather than infer temporality from one biopsy.
Show evidence (1 reference)
PMID:37843929 SUPPORT REVIEW SYNTHESIS Human Clinical
"In the endometrium, the diversion of healing towards a fibrotic outcome is often attributed to the obliteration of the stem cell reservoir during injury. However, this model is complicated by the observation that diverse cell populations may contribute to re-epithelialization of the endometrium"
Review explicitly challenges a simple complete-progenitor-loss account.
Which cells contribute to the fibrogenic effector pool in human adhesion disease?
KNOWLEDGE GAP gap_cellular_origins
Attached to
pathophysiology#Epithelial Mesenchymal Marker Shift pathophysiology#Endothelial Mesenchymal Marker Coexpression pathophysiology#Stromal Fibrogenic Activation
Partial EMT markers, CD31/alpha-SMA co-localization and transcriptomic intermediate states do not by themselves trace cellular origin. The rat experiment uses scraping plus LPS and has no endothelial lineage tracing. Lack of an EndMT conclusion in the human atlas is not a negative test of the hypothesis; resident stromal fibroblasts cannot be excluded.
Proposed experiments
Lineage-resolved fibrosis with matched human spatial validation
exp_lineage_resolved_fibrosis
Use inducible epithelial, endothelial and stromal lineage tracing plus selective perturbations in a defined injury model; quantify lineage-labelled matrix-producing cells. Spatial human RNA/protein coexpression can validate states but must not be treated as equivalent to prospective lineage tracing.
Show evidence (2 references)
PMID:34996477 SUPPORT PRIMARY RESULT Model Organism
"Immunofluorescence co-localization of CD31 and a-SMA showed that 14 days after moulding, double positive cells for CD31 and a-SMA could be clearly observed in the endometrium."
CD31/alpha-SMA co-localization in the rat injury model; no endothelial lineage tracing quantifies conversion into fibroblasts.
PMID:37302615 SUPPORT PRIMARY RESULT In Vitro
"Cell co-culture experiments showed that erastin-stimulated epithelial cell supernatants promoted fibrosis in HESCs (P < 0.05)."
Transferable supernatant activity supports epithelial-stromal coupling; the responsible mediator is unresolved in the accessible abstract.
How much of the human atlas signature reflects disease, hormonal preparation or cell recovery?
KNOWLEDGE GAP gap_human_niche_and_organoid_scope
Attached to
pathophysiology#Reduced Endometrial Epithelial Abundance pathophysiology#Reduced WNT Communication Signature pathophysiology#Reduced NOTCH Communication Signature
The human atlas included nine women with moderate or severe AS, five moderate and four severe, aged 34–42. AS biopsies were HRT-synchronized and obtained at least 1 cm from visible adhesions, while controls had natural cycles. Ten historical secretory controls and a twelve-sample WOI comparator overlap; they are not 22 independent controls. Recovered cell proportions, CellChat communication and RNAscope localization do not directly measure tissue-volume fractions, cell-death rates, cytokine secretion or angiogenesis. Organoids use three overlapping AS donors and three controls; P2 enrichment and XAV939 may mask differences. The paper provides no before/after cell-transplant efficacy comparison.
Show evidence (2 references)
PMID:37735465 SUPPORT PRIMARY RESULT Human Clinical
"A potential confounding element in this work may arise due to the comparison of AS patients undergoing hormonal replacement therapy (HRT) cycles with control patients undergoing natural cycles"
Authors acknowledge differential hormonal exposure.
PMID:37735465 SUPPORT PRIMARY RESULT Human Clinical
"The WOI control group comprised single-cell data from six single-cell transcriptomes obtained during the WOI from the GSE111976 dataset and six endometrial samples collected during the WOI from healthy donors."
Overlapping comparator datasets; not independent summed cohorts.
Which postoperative adjuncts improve live birth, beyond reducing visible adhesions?
KNOWLEDGE GAP gap_clinical_translation_and_adjuncts
Attached to
pathophysiology#Intrauterine Adhesion Formation pathophysiology#Reduced Receptive Endometrial Surface
Cavity scores, recurrence, menstrual recovery, pregnancy and live birth are distinct endpoints. Some barriers reduce short-term reformation, while comparative fertility benefit remains uncertain. The newer estrogen trial in selected ovulatory women with an IUD found no significant added benefit, without proving equivalence for every regimen. A 2026 hydrogel trial improves a short-term anatomical endpoint in the adhesiolysis subgroup; this does not establish long-term fertility or molecular regeneration. Animal drug timing and species-specific exposure preclude routine T3, rapamycin or ferrostatin treatment claims.
Proposed experiments
Controlled adjunct trial with reproductive follow-up
exp_adjunct_live_birth
Compare well-defined postoperative regimens with standardized baseline severity, second-look assessment and subsequent live-birth follow-up. Report infertility co-factors, repeat procedures, adverse effects and subgroup uncertainty; use anatomical outcomes as intermediate endpoints rather than validated fertility surrogates.
Show evidence (3 references)
PMID:28603474 SUPPORT REVIEW SYNTHESIS Other
"Semi-solid barriers such as hyaluronic acid and auto-cross-linked hyaluronic acid gel reduce adhesion reformation. At this time, their effect on post-treatment pregnancy rates is unknown. Grade A"
The 2017 recommendation concerns adhesion reformation rather than established live-birth benefit.
PMID:37396823 SUPPORT PRIMARY RESULT Human Clinical
"Of the women in usual care, 89.8% got pregnant within 3 years, and 67.8% got a living child; this was 83.6% and 60.0%, respectively, in the no-estrogen group (p = 0.33 and p = 0.39, respectively)."
Trial endpoints are nonsignificant, not proof of general equivalence.
PMID:42492609 SUPPORT PRIMARY RESULT Human Clinical
"In the adhesiolysis subgroup (n = 102), more participants in the hydrogel barrier arm were adhesion-free compared with controls (60.3% vs. 32.3%; odds ratio [OR] 3.19, 95% confidence interval [CI]: 1.29-7.90)"
Selected subgroup with anatomical outcome and uncertainty.
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Pathophysiology

18
Endometrial Basal Layer Injury
Pregnancy-related instrumentation, other uterine procedures or genital infection can damage the regenerative endometrial compartment. Injury context and residual tissue vary; this is not proof that every progenitor is eliminated.
basal layer of endometrium UBERON:0022355 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in basal layer of endometrium (UBERON:0022355). UBERON:0022355 is an anatomical location from the Uberon multi-species anatomy ontology. uterus UBERON:0000995 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in uterus (UBERON:0000995). UBERON:0000995 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Inflammatory Endometrial Niche Injury may establish an inflammatory repair environment; human atlas timing does not prove that the measured niche precedes adhesion formation.
Reduced Endometrial Epithelial Abundance Injury can reduce epithelial coverage, but the human atlas does not trace the time course or prove universal stem-cell depletion.
Excessive Endometrial Matrix Deposition Some injuries heal with scar rather than complete regeneration; multiple cellular intermediates remain unresolved.
Show evidence (1 reference)
PMID:30936754 SUPPORT REVIEW SYNTHESIS Human Clinical
"Intrauterine adhesions can develop from lesion of the basal layer of the endometrium caused by curettage of the newly pregnant uterus. The syndrome may also occur after hysteroscopic surgery, uterine artery embolization or uterine tuberculosis."
Names the basal-layer lesion as the origin and enumerates the four routes to it that this node covers.
Inflammatory Endometrial Niche
Selected human AS biopsies show altered immune-cell proportions and inflammatory expression/communication signatures. These observations do not directly measure cytokine secretion, immune recruitment rates or angiogenic capacity, and active endometritis was excluded from the atlas.
endometrium UBERON:0001295 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in endometrium (UBERON:0001295). UBERON:0001295 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Stromal Fibrogenic Activation An inflammatory niche may favor a fibrogenic stromal state; the cross-sectional atlas does not establish a specific cytokine as necessary.
Show evidence (1 reference)
PMID:37735465 SUPPORT PRIMARY RESULT Human Clinical
"We describe syndrome-associated alterations in cell-to-cell communication and gene expression profiles that support a dysfunctional pro-fibrotic, pro-inflammatory, and anti-angiogenic environment."
Cross-sectional transcriptional and inferred ligand-receptor context, without direct cytokine secretion or angiogenesis assays.
Reduced Endometrial Epithelial Abundance
The human single-cell atlas recovered a lower epithelial proportion from sampled AS endometrium. Dissociation, selection, hormonal treatment and clinical severity constrain interpretation; neither absolute tissue cell counts nor elimination of every stem/progenitor population was demonstrated.
endometrial epithelial cell CL:0002149 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves endometrial epithelial cell, annotated with epithelial cell of uterus (CL:0002149). CL:0002149 is a cell type from the Cell Ontology.
endometrium UBERON:0001295 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in endometrium (UBERON:0001295). UBERON:0001295 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Reduced Receptive Endometrial Surface Reduced epithelial coverage may limit the functional implantation surface; cell abundance and clinical receptivity were not experimentally separated.
Hypomenorrhea Loss of functioning endometrial surface may reduce menstrual shedding, independently of obstruction.
Amenorrhea Severe loss of functioning endometrium may prevent menstrual shedding; endocrine and outflow causes require separate assessment.
Show evidence (1 reference)
PMID:37735465 SUPPORT PRIMARY RESULT Human Clinical
"Our endometrial atlas highlights the loss of the endometrial epithelium, alterations to epithelial differentiation signaling pathways such as Wnt and Notch, and the appearance of characteristic epithelium expressing secretory leukocyte protease inhibitor during the window of implantation."
Human recovered-cell and transcriptional observations; cell proportions are not stereological tissue-volume measurements.
Reduced WNT Communication Signature
CellChat inferred reduced selected canonical and noncanonical WNT ligand-receptor interactions during the window of implantation. This is expression-based inference from selected human tissue, not direct pathway-activity measurement or a proven primary defect.
Altered epithelial differentiation within a dysfunctional niche
Wnt signaling pathway GO:0016055 ↕ DYSREGULATED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated Wnt signaling pathway (GO:0016055). GO:0016055 is a biological process from the Gene Ontology.
Downstream
Reduced Receptive Endometrial Surface Altered WNT communication may contribute to impaired epithelial differentiation and receptivity; composition, hormone exposure and causality are unresolved. Altered epithelial differentiation within a dysfunctional niche
Show evidence (1 reference)
PMID:37735465 SUPPORT PRIMARY RESULT Human Clinical
"specific absence of WNT7A-FZD6/LRP6 interactions in SOX9-epithelial cells and WNT5A-FZD6 interaction between stromal and luminal cell subtypes in AS"
Computational communication inference from human single-cell data.
Reduced NOTCH Communication Signature
The atlas inferred reduced JAG1-NOTCH2-associated communication in glandular and luminal populations. Receptor activation, lineage transition and pathway-specific rescue were not tested.
Altered epithelial differentiation within a dysfunctional niche
Notch signaling pathway GO:0007219 ↕ DYSREGULATED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated Notch signaling pathway (GO:0007219). GO:0007219 is a biological process from the Gene Ontology.
Downstream
Reduced Receptive Endometrial Surface A differentiation-related contribution is proposed; no intervention isolates NOTCH as the cause of human infertility. Altered epithelial differentiation within a dysfunctional niche
Show evidence (1 reference)
PMID:37735465 SUPPORT PRIMARY RESULT Human Clinical
"NOTCH pathway signaling significantly decreased in glandular, glandular secretory, and luminal subtypes, specifically in the JAG1-NOTCH2 ligand-receptor pair"
The source uses signaling language for a ligand-receptor expression inference.
Reduced Epithelial DIO2 Expression
Human IUA tissue shows lower DIO2 expression in selected assay subsets. Primary epithelial-cell knockdown and overexpression affect signaling and EMT-associated markers. Local tissue T3 showed a downward trend while serum thyroid measures were unchanged; this does not establish systemic hypothyroidism or measured DIO2 catalytic flux.
DIO2-associated autophagy changes amplify epithelial stress
endometrial epithelial cell CL:0002149 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves endometrial epithelial cell, annotated with epithelial cell of uterus (CL:0002149). CL:0002149 is a cell type from the Cell Ontology.
Experimental models
Primary endometrial epithelial DIO2 perturbation PRIMARY CELL CULTURE DIO2 si-1 reduces DIO2 RNA and protein.
Downstream
Increased ERK Phosphorylation DIO2 knockdown is associated with increased ERK phosphorylation in culture; the intervening mechanism is unresolved. DIO2-associated autophagy changes amplify epithelial stress
Show evidence (2 references)
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/ SUPPORT PRIMARY RESULT Human Clinical
"the mRNA and protein levels of DIO2 in endometria of IUA patients were significantly decreased to 40.97% and 30.80% of normal controls"
Human expression measurements in assay-specific tissue subsets; not a direct deiodinase activity assay.
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/ SUPPORT PRIMARY RESULT In Vitro
"Among them, si-1 was the most efficient siRNA which reduced the mRNA level to 39.75% and protein level to 61.86%"
Strongest screened DIO2 siRNA selected for downstream culture experiments.
Increased ERK Phosphorylation
DIO2 knockdown increases MAPK/ERK phosphorylation in cultured endometrial epithelial cells; human tissue also shows an associated phosphorylation pattern. This is not evidence of direct DIO2-to-ERK binding.
DIO2-associated autophagy changes amplify epithelial stress
Experimental models
Primary endometrial epithelial DIO2 perturbation PRIMARY CELL CULTURE DIO2 knockdown increases MAPK/ERK phosphorylation.
Downstream
Increased MTOR Phosphorylation MEK-pathway inhibition reduces the MTOR-associated phosphorylation state after DIO2 knockdown, supporting indirect pathway involvement. DIO2-associated autophagy changes amplify epithelial stress
Show evidence (1 reference)
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/ SUPPORT PRIMARY RESULT In Vitro
"significantly induced the phosphorylation of MAPK/ERK but not AMPK and AKT"
DIO2 knockdown-associated phosphorylation readout; intervening molecular events remain unresolved.
Increased MTOR Phosphorylation
Phospho-MTOR is increased in the DIO2-perturbed culture context and reduced after U0126 pretreatment. The assay is an activation-associated readout and does not establish every kinase-substrate intermediate.
DIO2-associated autophagy changes amplify epithelial stress
Downstream
Reduced Epithelial Autophagy MTOR-associated signaling is proposed to suppress autophagy in this experimental context; no selective ATG genetic epistasis establishes the complete route. DIO2-associated autophagy changes amplify epithelial stress
Show evidence (1 reference)
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/ SUPPORT PRIMARY RESULT In Vitro
"Meanwhile, we also observed that the activation of MTOR was inhibited by pre-treatment of U0126"
MEK-pathway inhibitor effect supports pathway involvement without demonstrating direct DIO2 binding or a direct kinase-substrate relationship.
Reduced Epithelial Autophagy
Human tissue and DIO2 culture experiments mainly show static autophagy-associated marker/structure changes. T3-associated chloroquine turnover provides dynamic flux support in culture; it should not be transferred to every human or DIO2 assay. Pharmacological effects support an autophagy-related hypothesis rather than a proven universal initiating lesion.
DIO2-associated autophagy changes amplify epithelial stress
endometrial epithelial cell CL:0002149 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves endometrial epithelial cell, annotated with epithelial cell of uterus (CL:0002149). CL:0002149 is a cell type from the Cell Ontology.
autophagy GO:0006914 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased autophagy (GO:0006914). GO:0006914 is a biological process from the Gene Ontology.
Experimental models
Primary epithelial pharmacological autophagy assay PRIMARY CELL CULTURE T3 increases autophagic turnover in the lysosomal-blockade comparison.
Animal models
Mouse uterine injury with autophagy-pathway drugs Mouse perturbs Autophagy-related drugs alter marker readouts in injured uterus.
Downstream
Epithelial Mesenchymal Marker Shift Chloroquine and rapamycin oppositely modify EMT-associated markers; drug pleiotropy and non-autophagic effects remain possible. DIO2-associated autophagy changes amplify epithelial stress
Show evidence (1 reference)
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/ SUPPORT PRIMARY RESULT In Vitro
"In endometrial epithelial cells (EECs), pharmacological inhibition of autophagy by chloroquine (CQ) promoted EEC-EMT, whereas enhanced autophagy by rapamycin extenuated this process."
Pharmacological effects on epithelial/mesenchymal markers; not genetic epistasis or lineage tracing.
Epithelial Mesenchymal Marker Shift
In experimental endometrial epithelial preparations, loss of epithelial markers and increases in mesenchymal markers indicate a partial EMT-like state. This does not show lineage-traced conversion into the complete human myofibroblast population or exclude resident stromal fibroblasts.
endometrial epithelial cell CL:0002149 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves endometrial epithelial cell, annotated with epithelial cell of uterus (CL:0002149). CL:0002149 is a cell type from the Cell Ontology.
epithelial to mesenchymal transition GO:0001837 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased epithelial to mesenchymal transition (GO:0001837). GO:0001837 is a biological process from the Gene Ontology.
Experimental models
Primary endometrial epithelial DIO2 perturbation PRIMARY CELL CULTURE Chloroquine removes the marker benefit associated with DIO2 overexpression.
Primary epithelial pharmacological autophagy assay PRIMARY CELL CULTURE Chloroquine and rapamycin have opposing EMT-marker effects.
Show evidence (2 references)
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/ SUPPORT PRIMARY RESULT In Vitro
"Importantly, the cytoprotective effect of DIO2 overexpression was lost in the CQ pre-treated EECs"
Pharmacological blockade supports an autophagy-related contribution to the marker phenotype, with drug pleiotropy unresolved.
PMID:37302615 SUPPORT PRIMARY RESULT In Vitro
"In vitro experiments showed that erastin-induced ferroptosis promoted EMT and fibrosis in endometrial epithelial cells (P < 0.05), but did not lead to pro-fibrotic differentiation in endometrial stromal cells (HESCs)."
Abstract-limited preparation-specific perturbation; epithelial and stromal responses differ.
Epithelial Ferroptotic Stress
A small human tissue comparison and pharmacological epithelial experiments implicate ferroptosis-related stress. The accessible abstract reports four severe IUA samples and four controls; detailed dosing, cell provenance and intervention specificity are not available from the full methods.
Ferroptotic epithelial stress promotes stromal fibrosis through transferable signals
endometrial epithelial cell CL:0002149 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves endometrial epithelial cell, annotated with epithelial cell of uterus (CL:0002149). CL:0002149 is a cell type from the Cell Ontology.
Animal models
Mouse ferroptosis perturbation in uterine injury Mouse perturbs Erastin and ferrostatin-1 perturb a ferroptosis-associated injury model.
Downstream
Epithelial Mesenchymal Marker Shift Erastin causes EMT-associated marker changes in epithelial preparations; this does not establish all injury-associated EMT as ferroptosis-dependent. Ferroptotic epithelial stress promotes stromal fibrosis through transferable signals
Epithelial Profibrotic Supernatant Activity Supernatant from erastin-stimulated epithelial cells carries fibrogenic activity; the responsible mediator remains unidentified in the accessible source. Ferroptotic epithelial stress promotes stromal fibrosis through transferable signals
Show evidence (2 references)
PMID:37302615 SUPPORT PRIMARY RESULT Human Clinical
"In the present study, we performed an RNA-seq of the endometria from 4 severe IUA patients and 4 normal controls."
Small human discovery comparison.
PMID:37302615 SUPPORT PRIMARY RESULT In Vitro
"In vitro experiments showed that erastin-induced ferroptosis promoted EMT and fibrosis in endometrial epithelial cells (P < 0.05), but did not lead to pro-fibrotic differentiation in endometrial stromal cells (HESCs)."
Abstract-limited preparation-specific perturbation; epithelial and stromal responses differ.
Epithelial Profibrotic Supernatant Activity
Erastin-stimulated epithelial-cell supernatant promotes a fibrotic response in HESCs, whereas direct erastin exposure did not produce the same stromal differentiation response. This distinguishes a transferable epithelial influence from direct stromal ferroptosis.
Ferroptotic epithelial stress promotes stromal fibrosis through transferable signals
Experimental models
Epithelial-supernatant stromal fibrosis assay CO CULTURE Supernatant carries transferable fibrogenic activity.
Downstream
Stromal Fibrogenic Activation The culture transfer experiment supports stromal response to epithelial supernatant without identifying the necessary secreted factor. Ferroptotic epithelial stress promotes stromal fibrosis through transferable signals
Show evidence (1 reference)
PMID:37302615 SUPPORT PRIMARY RESULT In Vitro
"Cell co-culture experiments showed that erastin-stimulated epithelial cell supernatants promoted fibrosis in HESCs (P < 0.05)."
Transferable supernatant activity supports epithelial-stromal coupling; the responsible mediator is unresolved in the accessible abstract.
Stromal Fibrogenic Activation
Endometrial stromal cells can develop a fibrogenic phenotype in experimental epithelial-stromal coupling. Resident stromal fibroblasts remain a plausible effector source; epithelial or endothelial marker coexpression does not establish their exclusive origin.
stromal cell of endometrium CL:0002255 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves stromal cell of endometrium (CL:0002255). CL:0002255 is a cell type from the Cell Ontology.
Experimental models
Epithelial-supernatant stromal fibrosis assay CO CULTURE HESC fibrotic response increases after stimulated epithelial supernatant.
Downstream
Excessive Endometrial Matrix Deposition Fibrogenic stromal activity can contribute to excess matrix; the relative human cellular sources and mediators remain unresolved.
Show evidence (1 reference)
PMID:37302615 SUPPORT PRIMARY RESULT In Vitro
"Cell co-culture experiments showed that erastin-stimulated epithelial cell supernatants promoted fibrosis in HESCs (P < 0.05)."
Transferable supernatant activity supports epithelial-stromal coupling; the responsible mediator is unresolved in the accessible abstract.
Endothelial Mesenchymal Marker Coexpression
In a rat curettage-plus-LPS injury model, CD31/alpha-SMA double-positive cells and changing CD31, alpha-SMA and vimentin levels are consistent with an EndMT-like state. No endothelial lineage tracing, source fraction, selective perturbation or human conversion experiment establishes a fibroblast origin.
Endothelial marker transitions may contribute to fibrosis
endothelial cell CL:0000115 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves endothelial cell (CL:0000115). CL:0000115 is a cell type from the Cell Ontology.
Animal models
Rat mechanical-plus-LPS uterine injury Rat measures CD31 and alpha-SMA double-positive cells are observed after injury.
Downstream
Excessive Endometrial Matrix Deposition An endothelial contribution is a model-derived hypothesis based on co-localized markers accompanying fibrosis, not proven lineage-mediated matrix production. Endothelial marker transitions may contribute to fibrosis
Show evidence (1 reference)
PMID:34996477 SUPPORT PRIMARY RESULT Model Organism
"Immunofluorescence co-localization of CD31 and a-SMA showed that 14 days after moulding, double positive cells for CD31 and a-SMA could be clearly observed in the endometrium."
CD31/alpha-SMA co-localization in the rat injury model; no endothelial lineage tracing quantifies conversion into fibroblasts.
Excessive Endometrial Matrix Deposition
After some injuries, collagen-rich fibrous connective tissue replaces portions of regenerative endometrium. Scar extent and residual regenerative capacity vary; this does not require complete irreversible depletion of all epithelial progenitors.
endometrium UBERON:0001295 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in endometrium (UBERON:0001295). UBERON:0001295 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Rat mechanical-plus-LPS uterine injury Rat partially recapitulates The injury model produces histological fibrosis, with model-specific inflammatory injury.
Mouse uterine injury with autophagy-pathway drugs Mouse partially recapitulates Histological fibrosis is attenuated under the reported rapamycin and T3 schedules.
Mouse ferroptosis perturbation in uterine injury Mouse partially recapitulates Ferrostatin-1 is associated with reduced experimental endometrial fibrosis.
Downstream
Intrauterine Adhesion Formation Fibrous tissue can bridge opposing endometrial surfaces and distort the cavity.
Reduced Receptive Endometrial Surface Replacement of functional endometrium can reduce suitable implantation surface, with additional functional and fertility factors remaining relevant.
Placenta accreta Prior endometrial scarring may disrupt the maternal placental interface; post-adhesiolysis cohort associations do not isolate this mechanism or prove that treatment itself is the sole cause.
Show evidence (1 reference)
PMID:39613882 SUPPORT REVIEW SYNTHESIS Human Clinical
"This damage leads to nonregenerative healing of endometrium resulting in replacement by fibrous connective tissue"
States the replacement of endometrium by fibrous connective tissue that this node asserts.
Intrauterine Adhesion Formation
Fibrous bands bridge uterine-cavity or endocervical surfaces. The lesion can partially or completely obstruct regions of the cavity; density, location and residual endometrium vary.
uterus UBERON:0000995 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in uterus (UBERON:0000995). UBERON:0000995 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Intrauterine adhesions The pathological bands correspond to the observed defining lesion.
Menstrual Outflow Obstruction Adhesions involving the outflow tract may obstruct menstrual drainage; not every adhesion produces obstruction.
Female infertility Cavity distortion or ostial obstruction may impede reproduction, alongside endometrial and unrelated fertility factors.
Show evidence (1 reference)
PMID:39613882 SUPPORT REVIEW SYNTHESIS Human Clinical
"which bring about the adherence of opposing endometrium to render the uterine cavity and/or cervical canal partially or completely obliterated"
Describes exactly the bridging-of-opposing-surfaces geometry and the cavity/cervical obliteration this node asserts.
Menstrual Outflow Obstruction
Adhesions can obstruct passage of menstrual effluent when functioning cycling endometrium remains. Reduced or absent external bleeding can coexist with retained blood and cyclic pain; normal menses does not exclude other clinically important adhesions.
uterus UBERON:0000995 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in uterus (UBERON:0000995). UBERON:0000995 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Hypomenorrhea Partial obstruction may reduce external menstrual flow.
Amenorrhea Complete outflow obstruction can prevent external bleeding.
Cyclic pelvic pain Trapped cycling menstrual effluent can produce recurrent pain.
Hematometra Outflow blockage may retain menstrual blood; it is not a universal manifestation.
Secondary endometriosis Retrograde menstruation is a proposed possible contributor to coexisting endometriosis, without a demonstrated disease-wide risk.
Show evidence (1 reference)
PMID:21437822 SUPPORT REVIEW SYNTHESIS Human Clinical
"Most women with IUA have amenorrhea or hypomenorrhea, but up to a fourth have painless menses of normal flow and duration. Those who have amenorrhea may also have cyclic pelvic pain caused by outflow obstruction. The accompanying retrograde menstruation may lead to endometriosis."
Single source for the whole node: the menstrual spectrum, the quarter-with-normal-menses caveat, the outflow-obstruction pain mechanism, and the retrograde-menstruation route to endometriosis.
Reduced Receptive Endometrial Surface
Scarring, reduced epithelial coverage and altered differentiation may reduce functional implantation surface. Hysteroscopic patency, transcriptional signatures and actual reproductive competence are distinct measurements; associated fertility impairment is not solely attributable to one pathway.
endometrium UBERON:0001295 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in endometrium (UBERON:0001295). UBERON:0001295 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Female infertility A deficient implantation environment may contribute to infertility; this is a clinical inference rather than pathway-specific causal proof.
Recurrent pregnancy loss Abnormal residual endometrium may contribute to pregnancy loss after implantation; infertility and miscarriage are distinct endpoints with multiple possible causes.
Show evidence (2 references)
PMID:37735465 SUPPORT PRIMARY RESULT Human Clinical
"Our endometrial atlas highlights the loss of the endometrial epithelium, alterations to epithelial differentiation signaling pathways such as Wnt and Notch, and the appearance of characteristic epithelium expressing secretory leukocyte protease inhibitor during the window of implantation."
Human recovered-cell and transcriptional observations; cell proportions are not stereological tissue-volume measurements.
PMID:30713131 SUPPORT REVIEW SYNTHESIS Human Clinical
"The pregnancy rate in women with severe adhesion was significantly lower than that in women with mild adhesion (P = 0.021)."
Selected post-adhesiolysis study synthesis supports a burden-outcome association, not an isolated assay of receptivity.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Asherman_Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

9
Genitourinary 5
Intrauterine adhesions OBLIGATE Uterine synechiae HP:0030712 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Uterine synechiae (HP:0030712). HP:0030712 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37735465 SUPPORT REVIEW SYNTHESIS Human Clinical
"Asherman's Syndrome is characterized by intrauterine adhesions or scarring, which cause infertility, menstrual abnormalities, and recurrent pregnancy loss."
Clinical review describes this finding; no separate disease-wide frequency is inferred.
Hypomenorrhea Abnormality of the menstrual cycle HP:0000140 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypomenorrhea, annotated with Abnormality of the menstrual cycle (HP:0000140). HP:0000140 is a phenotype from the Human Phenotype Ontology.
Coarse binding: no hpo term
No exact HPO hypomenorrhea label was found in live OLS search; the menstrual-cycle parent preserves the broader meaning.
Show evidence (1 reference)
PMID:21437822 SUPPORT REVIEW SYNTHESIS Human Clinical
"Most women with IUA have amenorrhea or hypomenorrhea, but up to a fourth have painless menses of normal flow and duration."
Clinical review describes this finding; no separate disease-wide frequency is inferred.
Amenorrhea HP:0000141 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Amenorrhea (HP:0000141). HP:0000141 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21437822 SUPPORT REVIEW SYNTHESIS Human Clinical
"Most women with IUA have amenorrhea or hypomenorrhea"
Clinical review describes this finding; no separate disease-wide frequency is inferred.
Female infertility HP:0008222 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Female infertility (HP:0008222). HP:0008222 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39613882 SUPPORT REVIEW SYNTHESIS Human Clinical
"IUA is a common cause of the refractory uterine infertility."
Clinical review describes this finding; no separate disease-wide frequency is inferred.
PMID:21437822 SUPPORT REVIEW SYNTHESIS Human Clinical
"In addition to abnormal menses, infertility and recurrent spontaneous abortion are common complaints."
Clinical review describes this finding; no separate disease-wide frequency is inferred.
Secondary endometriosis HP:0030127 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Endometriosis (HP:0030127). HP:0030127 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21437822 SUPPORT REVIEW SYNTHESIS Human Clinical
"The accompanying retrograde menstruation may lead to endometriosis."
Clinical review describes this finding; no separate disease-wide frequency is inferred.
Prenatal and Birth 1
Placenta accreta HP:0025654 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Placenta accreta (HP:0025654). HP:0025654 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30713131 SUPPORT REVIEW SYNTHESIS Human Clinical
"placenta accreta syndrome was 10.1% (95% CI: 8.6 to 11.8) in 23 studies"
A pooled post-adhesiolysis pregnancy complication, not an untreated disease frequency.
Constitutional 1
Cyclic pelvic pain HP:0034267 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pelvic pain (HP:0034267), qualified as temporality recurrent. HP:0034267 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (1 reference)
PMID:21437822 SUPPORT REVIEW SYNTHESIS Human Clinical
"Those who have amenorrhea may also have cyclic pelvic pain caused by outflow obstruction."
Clinical review describes this finding; no separate disease-wide frequency is inferred.
Other 2
Recurrent pregnancy loss
HP:0200067 Recurrent spontaneous abortion is outside the phenotypic-abnormality root used by the current dynamic enum; an unrelated fetal phenotype is not substituted.
Show evidence (1 reference)
PMID:21437822 SUPPORT REVIEW SYNTHESIS Human Clinical
"In addition to abnormal menses, infertility and recurrent spontaneous abortion are common complaints."
Clinical review describes this finding; no separate disease-wide frequency is inferred.
Hematometra
No exact hematometra HPO term was found in live OLS search.
Show evidence (1 reference)
PMID:28603474 SUPPORT REVIEW SYNTHESIS Human Clinical
"treatment should be considered only when there are signs or symptoms of pain, infertility, recurrent pregnancy loss, or menstrual abnormalities including hematometra."
Guideline identifies retained menstrual blood among clinically relevant presentations.
💊

Medical Actions

9
Hysteroscopic adhesiolysis
Action: HysteroscopyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Hysteroscopy (NCIT:C148437). NCIT:C148437 is a clinical intervention from the NCI Thesaurus. NCIT:C148437
Direct-vision division of symptomatic adhesions is the standard lesion-directed approach (AAGL/ESGE Level B). Severe or extensive disease warrants experienced hysteroscopic care. Cold scissors avoid thermal injury, but randomized evidence does not establish superiority of one instrument. Blind curettage and blind probing are not supported. Image guidance may help selected difficult procedures without demonstrated prevention of perforation.
Mechanism Target:
INHIBITS Intrauterine Adhesion Formation — Division of existing bridging adhesions restores cavity access; it does not assure recovered endometrial function or fertility.
Show evidence (1 reference)
PMID:28603474 SUPPORT REVIEW SYNTHESIS Other
"Hysteroscopic lysis of adhesions by direct vision and a tool for adhesiolysis is the recommended approach for symptomatic IUAs. Level B"
Recommended lesion-directed treatment for symptomatic disease.
Show evidence (2 references)
PMID:28603474 SUPPORT REVIEW SYNTHESIS Other
"Hysteroscopic lysis of adhesions by direct vision and a tool for adhesiolysis is the recommended approach for symptomatic IUAs. Level B"
Recommended lesion-directed treatment for symptomatic disease.
PMID:28603474 SUPPORT REVIEW SYNTHESIS Other
"There is no evidence to support the use of blind dilation and curettage. Level C."
Avoid replacing visual treatment with blind curettage.
Temporary intrauterine physical barriers
An inert large-surface-area IUD, balloon, stent or catheter may separate healing surfaces after adhesiolysis. The guideline grades reduced reformation A but notes limited subsequent fertility data; device and duration depend on clinical context. Copper-containing and progestin-containing IUDs should not be substituted for the recommended inert device.
Mechanism Target:
INHIBITS Intrauterine Adhesion Formation — Temporary separation aims to reduce postoperative adhesion reformation.
Show evidence (1 reference)
PMID:28603474 SUPPORT REVIEW SYNTHESIS Other
"The use of an IUD, stent, or catheter appears to reduce the rate of postoperative adhesion reformation. There are limited data regarding subsequent fertility outcomes when these barriers are used. Grade A"
Recurrence and fertility are distinct outcomes.
Show evidence (2 references)
PMID:28603474 SUPPORT REVIEW SYNTHESIS Other
"The use of an IUD, stent, or catheter appears to reduce the rate of postoperative adhesion reformation. There are limited data regarding subsequent fertility outcomes when these barriers are used. Grade A"
Recurrence and fertility are distinct outcomes.
PMID:28603474 SUPPORT REVIEW SYNTHESIS Other
"If an IUD is used postoperatively, it should be inert and have a large surface area such as a Lippes loop. Intrauterine devices that contain progestin or copper should not be used after surgical division of IUAs. Grade C"
Device-specific limitation.
Hyaluronic-acid adhesion barriers
Agent: hyaluronic acid CHEBI:16336 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses hyaluronic acid (CHEBI:16336). CHEBI:16336 is a therapeutic agent from Chemical Entities of Biological Interest.
Selected postoperative semi-solid barriers can reduce adhesion reformation, but the size of benefit and reproductive outcomes vary by product, procedure and comparator. A network meta-analysis of 21 randomized trials and 2,406 patients did not establish a significant clinical-pregnancy advantage across the compared adjuvants; ranking changes in adhesion scores is not a live-birth recommendation.
Mechanism Target:
INHIBITS Intrauterine Adhesion Formation — Barrier-associated reduction in reformation does not prove regeneration of receptive endometrium.
Show evidence (1 reference)
PMID:28603474 SUPPORT REVIEW SYNTHESIS Other
"Semi-solid barriers such as hyaluronic acid and auto-cross-linked hyaluronic acid gel reduce adhesion reformation. At this time, their effect on post-treatment pregnancy rates is unknown. Grade A"
The 2017 recommendation concerns adhesion reformation rather than established live-birth benefit.
Show evidence (2 references)
PMID:28603474 SUPPORT REVIEW SYNTHESIS Other
"Semi-solid barriers such as hyaluronic acid and auto-cross-linked hyaluronic acid gel reduce adhesion reformation. At this time, their effect on post-treatment pregnancy rates is unknown. Grade A"
The 2017 recommendation concerns adhesion reformation rather than established live-birth benefit.
PMID:38493418 SUPPORT REVIEW SYNTHESIS Human Clinical
"21 randomized controlled trials involving 2406 patients"
Network review population; heterogeneous adjuncts and endpoints.
Postoperative estrogen with or without progestin
The 2017 guideline gives a Grade B recommendation that estrogen may reduce recurrence. A later single-centre randomized trial found no significant adhesion, pregnancy or living-child benefit from adding estrogen in selected women with previously regular ovulatory cycles, successful adhesiolysis and an inert IUD in both groups. Of 114 analyzed women, second-look recurrence was 16/59 versus 14/55; living-child outcomes were 40/59 versus 33/55. Wide uncertainty, selection and the shared barrier limit extrapolation to every regimen or anovulatory patient. Side effects were frequent in the estrogen group. These results do not demonstrate equivalence or a universal regenerative effect.
Show evidence (2 references)
PMID:28603474 SUPPORT REVIEW SYNTHESIS Other
"Following hysteroscopic-directed adhesiolysis, postoperative hormone treatment using estrogen, with or without progestin, may reduce recurrence of IUAs. Grade B"
Older conditional recommendation.
PMID:37396823 SUPPORT PRIMARY RESULT Human Clinical
"Of the women in usual care, 89.8% got pregnant within 3 years, and 67.8% got a living child; this was 83.6% and 60.0%, respectively, in the no-estrogen group (p = 0.33 and p = 0.39, respectively)."
Trial endpoints are nonsignificant, not proof of general equivalence.
Post-treatment cavity reassessment
Reassess the uterine cavity, preferably hysteroscopically (Grade B), because recurrence may require further treatment. Timing is individualized; the guideline discusses reassessment after two to three cycles and earlier second-look approaches. Surveillance identifies recurrence rather than independently restoring endometrial function.
Show evidence (1 reference)
PMID:28603474 SUPPORT REVIEW SYNTHESIS Other
"Follow-up assessment of the uterine cavity after treatment of IUAs is recommended, preferably with hysteroscopy. Grade B"
Recommended follow-up after treatment.
Pregnancy and fertility follow-up
Evaluate other infertility factors when conception does not follow cavity restoration. Subsequent pregnancies warrant attention to abnormal placentation, pregnancy loss, prematurity and retained placenta. Post-adhesiolysis cohort risks do not establish a fixed outcome for an individual pregnancy.
Show evidence (1 reference)
PMID:30713131 SUPPORT REVIEW SYNTHESIS Human Clinical
"placenta accreta syndrome was 10.1% (95% CI: 8.6 to 11.8) in 23 studies"
Selected treated-pregnancy evidence supports attention to placentation; it does not test a particular surveillance protocol.
Treatment of confirmed genital tuberculosis
Agent: rifampicin CHEBI:28077 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses rifampicin (CHEBI:28077). CHEBI:28077 is a therapeutic agent from Chemical Entities of Biological Interest. isoniazide CHEBI:6030 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses isoniazide (CHEBI:6030). CHEBI:6030 is a therapeutic agent from Chemical Entities of Biological Interest. pyrazinamide CHEBI:45285 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses pyrazinamide, annotated with pyrazinecarboxamide (CHEBI:45285). CHEBI:45285 is a therapeutic agent from Chemical Entities of Biological Interest. ethambutol CHEBI:4877 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses ethambutol (CHEBI:4877). CHEBI:4877 is a therapeutic agent from Chemical Entities of Biological Interest.
Treat confirmed genital tuberculosis with appropriate multidrug antimicrobial care and infectious-disease input; adhesions and infertility may persist after microbiological treatment. One reported patient received two months of rifampin, isoniazid, pyrazinamide and ethambutol, followed by rifampin/isoniazid, with an extension after persistent acid-fast staining despite negative culture. Cyclic spotting returned only during subsequent estrogen priming; neither antibiotic-only menstrual recovery nor restored fertility was demonstrated.
Show evidence (1 reference)
PMID:31388435 SUPPORT PRIMARY RESULT Human Clinical
"At this time, the patient was started on 2-month course of 4-drug Rifampin, Isoniazid, Pyrazinamide, and Ethambutol (RIPE) therapy followed by 4 months of ri- fampin and isoniazid."
Actual reported regimen; individual management is not a universally validated AS treatment protocol.
No routine perioperative antibiotic recommendation
The AAGL/ESGE guideline finds insufficient evidence for or against antibiotics specifically to prevent postoperative adhesions. This uncertainty does not replace treatment of a documented infection or other independently indicated prophylaxis.
Show evidence (1 reference)
PMID:28603474 SUPPORT REVIEW SYNTHESIS Other
"There is no evidence to support or refute the use of preoperative, intraoperative, or postoperative antibiotic therapy in surgical treatment of IUAs. Grade C"
No established adhesion-prevention benefit.
Investigational regenerative and molecular therapies
Stem-cell approaches and agents intended to alter vascular flow remain research interventions. Animal T3, rapamycin and ferrostatin findings do not establish human fertility benefit or a clinical regimen. Putative stem-cell benefit may involve niche/paracrine changes rather than durable replacement of all missing epithelial progenitors; controlled clinical efficacy remains a separate question.
Show evidence (2 references)
PMID:28603474 SUPPORT REVIEW SYNTHESIS Other
"Stem cell treatment may ultimately provide an effective adjuvant approach to the treatment of Asherman syndrome; however, evidence is very limited and this treatment should not be offered outside of rigorous research protocols. Grade C"
Research-only status in the guideline.
PMID:28603474 SUPPORT REVIEW SYNTHESIS Other
"The role of medications designed as adjuvants to improve vascular flow to the endometrium has not been established. Consequently, they should not be used outside of rigorous research protocols. Grade C"
No established vascular adjunct regimen.
🔬

Biochemical Markers

1
SLPI-positive endometrial epithelial state (INCREASED)
Context: Research biopsy single-cell RNA and RNAscope in the secretory/window-of-implantation setting
Show evidence (1 reference)
PMID:37735465 SUPPORT PRIMARY RESULT Human Clinical
"RNAscope experiments localized SLPI+ cells to the luminal and glandular epithelium of AS patients"
Localization of a research transcriptomic state, not a validated diagnostic test.
🔬

Diagnosis

5
Hysteroscopy
Direct visualization is the diagnostic reference standard when the cavity is accessible. Record location, extent, density and residual endometrium; it can permit concurrent adhesiolysis. Severe obliteration requires specialist assessment.
Hysteroscopy NCIT:C148437 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:28603474 SUPPORT REVIEW SYNTHESIS Other
"Hysteroscopy is the most accurate method for diagnosis of IUAs and should be the investigation of choice when available. Level B."
AAGL/ESGE recommendation.
Contrast cavity imaging
Saline/gel infusion sonography or hysterosalpingography may assess the cavity when hysteroscopy is unavailable or during initial evaluation. HSG also assesses tubal patency. False-positive and false-negative findings limit replacement of hysteroscopy.
Show evidence (1 reference)
PMID:28603474 SUPPORT REVIEW SYNTHESIS Other
"If hysteroscopy is not available, HSG and SHG are reasonable alternatives. Level B."
Alternative cavity assessment with imperfect accuracy.
Selective MRI in an inaccessible cavity
MRI is not a routine diagnostic requirement. The 2017 guideline restricts it to research, while the 2019 review describes possible value in rare totally obstructed cavities where standard cavity tests are limited; selection is specialist-dependent.
Show evidence (2 references)
PMID:28603474 SUPPORT REVIEW SYNTHESIS Other
"Magnetic resonance imaging should not be used for diagnosis of IUAs outside of clinical research studies. Level C."
Guideline restriction.
PMID:30936754 SUPPORT REVIEW SYNTHESIS Human Clinical
"In these rare cases MRI can be valuable, although too expensive as a routine diagnostic tool."
Later review discusses selective use after total obstruction.
Amenorrhea and fertility evaluation
Evaluate pregnancy and endocrine causes of amenorrhea and other contributors to infertility. Failure to bleed after an estrogen-progesterone challenge with otherwise intact ovarian-axis function supports an outflow/endometrial cause but is not itself definitive proof of adhesions.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK448088/ SUPPORT REVIEW SYNTHESIS Human Clinical
"The failure to induce menses despite stimulating the endometrium with an estrogen-progesterone challenge, in a patient with secondary amenorrhea, with normal hypothalamic-pituitary-ovarian functions and hormone levels, points towards the diagnosis of Asherman's syndrome."
Clinical differential assessment.
Endometrial testing for suspected genital tuberculosis
When exposure and clinical findings suggest infection, endometrial histology, acid-fast staining and mycobacterial culture can support the diagnosis. A negative chest radiograph does not exclude genital tuberculosis.
Show evidence (1 reference)
PMID:31388435 SUPPORT PRIMARY RESULT Human Clinical
"necrotizing granulomas with acid- fast bacilli positive and culture positive for Mycobac- terium tuberculosis"
Confirmed infection in a selected patient, not universal screening or assay sensitivity.
📈

Progression

2
Recurrence after adhesiolysis
Adhesions may recur after technically successful cavity restoration. More extensive baseline disease generally requires more treatment; an open cavity does not guarantee recovered endometrial function or fertility.
Show evidence (1 reference)
PMID:28603474 SUPPORT REVIEW SYNTHESIS Human Clinical
"recurrence is common and may occur in 30 to 66% of women treated for IUAs"
A guideline range from selected treated cohorts rather than a fixed patient prognosis.
Reproductive outcomes after adhesiolysis
A 2019 systematic review of 54 studies and 4,640 women of varying quality pooled pregnancy at 50.7% across 53 studies. Early loss, mid-trimester loss, ectopic pregnancy, cervical incompetence and abnormal placentation were reported in different subsets. These outcomes cannot be summed or treated as one longitudinal sequence or as frequencies in untreated disease. Residual severity, other fertility factors, follow-up and treatment protocols differ.
Show evidence (3 references)
PMID:30713131 SUPPORT REVIEW SYNTHESIS Human Clinical
"There were 54 studies (4640 women) of varying quality."
Heterogeneous treated-study base.
PMID:30713131 SUPPORT REVIEW SYNTHESIS Human Clinical
"The pooled rate of pregnancy was 50.7%"
Post-treatment pooled pregnancy proportion.
PMID:30713131 SUPPORT REVIEW SYNTHESIS Human Clinical
"early pregnancy loss was 17.7% (95% CI: 15.9 to 19.6) in 31 studies, ectopic pregnancy (EP) was 4.2% (95% CI: 2.8 to 6.3) in 9 studies, mid-trimester loss (MTL) was 11.5% (95% CI: 7.6 to 17.8) in 7 studies, cervical incompetence was 12.5% (95% CI: 3.3 to 33.5) in 2 studies and placenta accreta..."
Each complication uses a distinct study subset; no disease-wide phenotype band is inferred.
📊

Prevalence

1
Women evaluated by hysteroscopy within 12 months of a miscarriage
Period Prevalence 19100.0 per 100,000 (12800.0–27500.0) >1 in 1,000
The 2014 review included 912 women in ten prospective studies evaluated by hysteroscopy within twelve months of miscarriage after spontaneous expulsion or medical/surgical management. There were 183 detected adhesions; the pooled prevalence was 19.1% (95% CI 12.8–27.5%). Severity was reported for 124, of whom 58.1% had mild adhesions. This is selected post-miscarriage IUA prevalence, including findings of uncertain clinical importance, not general-population prevalence of symptomatic Asherman syndrome.
Show evidence (2 references)
PMID:24082042 SUPPORT REVIEW SYNTHESIS Human Clinical
"IUAs were detected in 183 women, resulting in a pooled prevalence of 19.1% [95% confidence interval (CI): 12.8-27.5%]."
The pooled point estimate and interval recorded in this record.
PMID:24082042 SUPPORT REVIEW SYNTHESIS Human Clinical
"In more than half of these, the severity and extent of the adhesions was mild, with unknown clinical relevance."
Deliberate limit on the number above: the pooled figure counts hysteroscopic lesions, most of them mild, and must not be read as the prevalence of symptomatic Asherman syndrome.
🌍

Epidemiology

3
Repeated uterine instrumentation
Repeated miscarriage and dilation/curettage are associated with adhesion detection. The number of curettages may contribute, but pre-existing uterine conditions and indications for repeated treatment complicate causal attribution.
Show evidence (1 reference)
PMID:24082042 SUPPORT REVIEW SYNTHESIS Human Clinical
"The number of dilatation and curettage (D&C) procedures seemed to be the main driver behind these associations."
The systematic review qualifies the proposed mediator.
Genital tuberculosis
Genital tuberculosis can injure the endometrium and cause adhesions, often alongside tubal disease. Consider exposure and regional context when clinically indicated; tuberculosis is not the cause of most post-instrumentation cases.
Show evidence (1 reference)
PMID:31388435 SUPPORT PRIMARY RESULT Human Clinical
"We present a case of genital tuberculosis causing Asherman's syndrome and resultant infertility."
One infection-associated case report; no population rate is inferred.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Asherman_Syndrome:

Endocrine or ovarian causes of amenorrhea
Overlapping Features Pregnancy, thyroid, hypothalamic/pituitary and ovarian dysfunction require assessment; ovarian-axis tests and cavity evaluation distinguish overlapping presentations.
Distinguishing Features
  • Endocrine abnormalities or pregnancy without a required adhesion lesion
Isolated cervical stenosis
Overlapping Features An outflow lesion may cause amenorrhea or cyclic pain without endometrial bridging adhesions throughout the cavity.
Distinguishing Features
  • Localized cervical obstruction with an otherwise preserved cavity
Endometriosis or adenomyosis
Overlapping Features These can cause pain and infertility and may coexist with adhesion disease. They do not require intrauterine synechiae; a patent cavity does not exclude either condition.
Distinguishing Features
  • Endometriotic lesions outside the cavity or endometrial-type tissue within myometrium
🔬

Clinical Trials

1
NCT05394662 PHASE_III COMPLETED
Juveena Hydrogel barrier trial after adhesiolysis or myomectomy. The 2026 report randomized 150 participants (99 hydrogel, 51 control), including 102 undergoing adhesiolysis. In that subgroup, 60.3% versus 32.3% were adhesion-free at second look (OR 3.19, 95% CI 1.29–7.90). The mixed-procedure study and short-term hysteroscopic endpoint do not establish live-birth efficacy; reported device-safety follow-up extended through three weeks. The abstract does not establish that this product is interchangeable with all hyaluronic-acid barriers.
Show evidence (3 references)
clinicaltrials:NCT05394662 SUPPORT PRIMARY RESULT Other
"This study is to determine whether intrauterine instillation of Juveena hydrogel following adhesiogenic hysteroscopic procedures (TCGP + Juveena) can safely and effectively reduce the incidence and severity of intrauterine adhesions (IUA) compared to TCGP alone."
Registry identity/design; status and phase verified separately through the live API on 2026-09-21.
PMID:42492609 SUPPORT PRIMARY RESULT Human Clinical
"Between August 2022 and January 2025, 150 participants were randomized (hydrogel barrier: n = 99; control: n = 51)."
Published randomized study denominator.
PMID:42492609 SUPPORT PRIMARY RESULT Human Clinical
"In the adhesiolysis subgroup (n = 102), more participants in the hydrogel barrier arm were adhesion-free compared with controls (60.3% vs. 32.3%; odds ratio [OR] 3.19, 95% confidence interval [CI]: 1.29-7.90)"
Selected subgroup with anatomical outcome and uncertainty.
🧫

Experimental Models

4
Primary endometrial epithelial DIO2 perturbation PRIMARY_CELL_CULTURE
The strongest of three screened DIO2 siRNAs and a DIO2 overexpression construct alter ERK/MTOR phosphorylation, autophagy-associated markers and epithelial/mesenchymal markers. Chloroquine blockade and U0126 pretreatment test pharmacological pathway dependence.
endometrial epithelial cell CL:0002149 Cell Ontology (CL) Relation: this experimental model uses this cell type This experimental model uses endometrial epithelial cell, annotated with epithelial cell of uterus (CL:0002149). CL:0002149 is a cell type from the Cell Ontology.
Organism
Homo sapiens NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Cell source
Primary human endometrial epithelial cultures; individual donor independence is not established for every assay
Publication
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/
Pathograph links
Reduced Epithelial DIO2 Expression perturbs DIO2 si-1 reduces DIO2 RNA and protein.
Readouts
DIO2 expression after si-1
Direction: DECREASED
Interpretation: DIO2 si-1 reduces DIO2 RNA and protein.
Show evidence (1 reference)
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/ SUPPORT PRIMARY RESULT In Vitro
"Among them, si-1 was the most efficient siRNA which reduced the mRNA level to 39.75% and protein level to 61.86%"
Strongest screened DIO2 siRNA selected for downstream culture experiments.
Show evidence (1 reference)
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/ SUPPORT PRIMARY RESULT In Vitro
"Among them, si-1 was the most efficient siRNA which reduced the mRNA level to 39.75% and protein level to 61.86%"
Strongest screened DIO2 siRNA selected for downstream culture experiments.
Increased ERK Phosphorylation measures DIO2 knockdown increases MAPK/ERK phosphorylation.
Readouts
ERK phosphorylation
Direction: INCREASED
Interpretation: DIO2 knockdown increases MAPK/ERK phosphorylation.
Show evidence (1 reference)
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/ SUPPORT PRIMARY RESULT In Vitro
"significantly induced the phosphorylation of MAPK/ERK but not AMPK and AKT"
DIO2 knockdown-associated phosphorylation readout; intervening molecular events remain unresolved.
Show evidence (1 reference)
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/ SUPPORT PRIMARY RESULT In Vitro
"significantly induced the phosphorylation of MAPK/ERK but not AMPK and AKT"
DIO2 knockdown-associated phosphorylation readout; intervening molecular events remain unresolved.
Epithelial Mesenchymal Marker Shift measures Chloroquine removes the marker benefit associated with DIO2 overexpression.
Show evidence (1 reference)
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/ SUPPORT PRIMARY RESULT In Vitro
"Importantly, the cytoprotective effect of DIO2 overexpression was lost in the CQ pre-treated EECs"
Pharmacological blockade supports an autophagy-related contribution to the marker phenotype, with drug pleiotropy unresolved.
No siRNA-resistant rescue, catalytic-dead comparison, direct DIO2-to-ERK binding assay or genetic ATG epistasis is reported. Most DIO2 assays are static marker/structure measurements. The paper uses Ishikawa cells for CCK-8 viability, so that reassurance is not assigned to all primary EEC exposures. Marker shifts do not trace a human fibroblast lineage.
Show evidence (3 references)
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/ SUPPORT PRIMARY RESULT In Vitro
"Among them, si-1 was the most efficient siRNA which reduced the mRNA level to 39.75% and protein level to 61.86%"
Strongest screened DIO2 siRNA selected for downstream culture experiments.
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/ SUPPORT PRIMARY RESULT In Vitro
"significantly induced the phosphorylation of MAPK/ERK but not AMPK and AKT"
DIO2 knockdown-associated phosphorylation readout; intervening molecular events remain unresolved.
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/ SUPPORT PRIMARY RESULT In Vitro
"Importantly, the cytoprotective effect of DIO2 overexpression was lost in the CQ pre-treated EECs"
Pharmacological blockade supports an autophagy-related contribution to the marker phenotype, with drug pleiotropy unresolved.
Primary epithelial pharmacological autophagy assay PRIMARY_CELL_CULTURE
Chloroquine, rapamycin and T3 perturb autophagy-associated and epithelial/mesenchymal readouts. The T3 plus chloroquine comparison is the explicit dynamic turnover experiment.
Organism
Homo sapiens NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Cell source
Primary human endometrial epithelial cells
Publication
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/
Pathograph links
Reduced Epithelial Autophagy perturbs T3 increases autophagic turnover in the lysosomal-blockade comparison.
Readouts
T3-associated autophagic flux
Direction: INCREASED
Interpretation: T3 increases autophagic turnover in the lysosomal-blockade comparison.
Show evidence (1 reference)
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/ SUPPORT PRIMARY RESULT In Vitro
"CQ and T3 treatment significantly increased LC3B-II levels compared to T3 or CQ alone suggesting that T3 increased autophagic flux in EECs."
Lysosomal-blockade turnover supports dynamic T3-associated flux in culture; other marker assays are not equivalent.
Show evidence (1 reference)
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/ SUPPORT PRIMARY RESULT In Vitro
"CQ and T3 treatment significantly increased LC3B-II levels compared to T3 or CQ alone suggesting that T3 increased autophagic flux in EECs."
Lysosomal-blockade turnover supports dynamic T3-associated flux in culture; other marker assays are not equivalent.
Epithelial Mesenchymal Marker Shift measures Chloroquine and rapamycin have opposing EMT-marker effects.
Show evidence (1 reference)
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/ SUPPORT PRIMARY RESULT In Vitro
"In endometrial epithelial cells (EECs), pharmacological inhibition of autophagy by chloroquine (CQ) promoted EEC-EMT, whereas enhanced autophagy by rapamycin extenuated this process."
Pharmacological effects on epithelial/mesenchymal markers; not genetic epistasis or lineage tracing.
Drug effects support pharmacological mediation with unresolved pleiotropy. No human fertility endpoint or transplant outcome is measured.
Show evidence (2 references)
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/ SUPPORT PRIMARY RESULT In Vitro
"In endometrial epithelial cells (EECs), pharmacological inhibition of autophagy by chloroquine (CQ) promoted EEC-EMT, whereas enhanced autophagy by rapamycin extenuated this process."
Pharmacological effects on epithelial/mesenchymal markers; not genetic epistasis or lineage tracing.
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/ SUPPORT PRIMARY RESULT In Vitro
"CQ and T3 treatment significantly increased LC3B-II levels compared to T3 or CQ alone suggesting that T3 increased autophagic flux in EECs."
Lysosomal-blockade turnover supports dynamic T3-associated flux in culture; other marker assays are not equivalent.
Epithelial-supernatant stromal fibrosis assay CO_CULTURE
Erastin-induced epithelial stress promotes EMT/fibrosis markers, whereas direct erastin does not induce stromal fibrogenic differentiation. Transfer of stimulated epithelial supernatant promotes the stromal response.
Cell source
Endometrial epithelial and human endometrial stromal preparations reported in the abstract; further provenance unavailable
Publication
PMID:37302615
Pathograph links
Epithelial Profibrotic Supernatant Activity measures Supernatant carries transferable fibrogenic activity.
Show evidence (1 reference)
PMID:37302615 SUPPORT PRIMARY RESULT In Vitro
"Cell co-culture experiments showed that erastin-stimulated epithelial cell supernatants promoted fibrosis in HESCs (P < 0.05)."
Transferable supernatant activity supports epithelial-stromal coupling; the responsible mediator is unresolved in the accessible abstract.
Stromal Fibrogenic Activation perturbs HESC fibrotic response increases after stimulated epithelial supernatant.
Readouts
Stromal fibrotic response
Direction: INCREASED
Interpretation: HESC fibrotic response increases after stimulated epithelial supernatant.
Show evidence (1 reference)
PMID:37302615 SUPPORT PRIMARY RESULT In Vitro
"Cell co-culture experiments showed that erastin-stimulated epithelial cell supernatants promoted fibrosis in HESCs (P < 0.05)."
Transferable supernatant activity supports epithelial-stromal coupling; the responsible mediator is unresolved in the accessible abstract.
Show evidence (1 reference)
PMID:37302615 SUPPORT PRIMARY RESULT In Vitro
"Cell co-culture experiments showed that erastin-stimulated epithelial cell supernatants promoted fibrosis in HESCs (P < 0.05)."
Transferable supernatant activity supports epithelial-stromal coupling; the responsible mediator is unresolved in the accessible abstract.
The abstract calls this a co-culture experiment; the accessible record does not establish simultaneous contact culture, the necessary soluble mediator, dose or donor replication. No mediator-neutralization result or direct epithelial lineage conversion is inferred.
Show evidence (2 references)
PMID:37302615 SUPPORT PRIMARY RESULT In Vitro
"In vitro experiments showed that erastin-induced ferroptosis promoted EMT and fibrosis in endometrial epithelial cells (P < 0.05), but did not lead to pro-fibrotic differentiation in endometrial stromal cells (HESCs)."
Abstract-limited preparation-specific perturbation; epithelial and stromal responses differ.
PMID:37302615 SUPPORT PRIMARY RESULT In Vitro
"Cell co-culture experiments showed that erastin-stimulated epithelial cell supernatants promoted fibrosis in HESCs (P < 0.05)."
Transferable supernatant activity supports epithelial-stromal coupling; the responsible mediator is unresolved in the accessible abstract.
Patient-derived endometrial epithelial organoids ORGANOID
Hormone-treated passage-two organoids were profiled by single-cell RNA sequencing. Transcriptomic identities were assigned with a reference-trained classifier and compared between groups. AS organoid transcriptomic profiles differed from controls, particularly in glandular secretory epithelium; that result is not equated with the tissue-derived reduced-WNT communication signature.
Organism
Homo sapiens NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Cell source
Three Asherman and three healthy-control endometrial donors; Asherman donors overlap the tissue cohort
Publication
PMID:37735465
Passage-two culture enriches organoid-forming cells. WNT inhibitor XAV939 in culture may mask differences; hormonal and selection effects limit extrapolation to untreated tissue. These assays neither trace progenitor fate nor show pathway-specific rescue or clinical cell-therapy efficacy.
Show evidence (3 references)
PMID:37735465 SUPPORT PRIMARY RESULT In Vitro
"Organoids were generated from AS patients’ endometrium (n = 3) and from healthy control (n = 3) endometrium"
Three AS organoid donors overlap the nine-person human atlas cohort.
PMID:37735465 SUPPORT PRIMARY RESULT In Vitro
"Additionally, we obtained single-cell EEO results at P2, with a technical enrichment of organoid-forming cells, while the presence of XAV939 (a WNT inhibitor) in the EEO culture media may mask significant differences."
Authors explicitly limit interpretation of the organoid comparison.
PMID:37735465 SUPPORT PRIMARY RESULT In Vitro
"the transcriptomic profile of AS EEO cells became significantly different from WOI control EEO cells and in vivo counterparts, especially in the glandular secretory epithelium"
Actual organoid transcriptional comparison; this does not establish an isolated WNT readout.
🐁

Animal Models

3
Rat mechanical-plus-LPS uterine injury
Uterine scraping plus an intrauterine LPS-bearing thread retained for 48 hours produces fibrosis, reduced glands and adhesion-associated histology. Observations at days 3, 7, 14 and 28 include CD31/alpha-SMA co-localization at day 14.
Species
Rat
Background
Eight-week-old female Sprague-Dawley rats
Publication
PMID:34996477
Pathograph links
Endothelial Mesenchymal Marker Coexpression measures CD31 and alpha-SMA double-positive cells are observed after injury.
Readouts
CD31/alpha-SMA co-localization
Direction: INCREASED
Interpretation: CD31 and alpha-SMA double-positive cells are observed after injury.
Show evidence (1 reference)
PMID:34996477 SUPPORT PRIMARY RESULT Model Organism
"Immunofluorescence co-localization of CD31 and a-SMA showed that 14 days after moulding, double positive cells for CD31 and a-SMA could be clearly observed in the endometrium."
CD31/alpha-SMA co-localization in the rat injury model; no endothelial lineage tracing quantifies conversion into fibroblasts.
Show evidence (1 reference)
PMID:34996477 SUPPORT PRIMARY RESULT Model Organism
"Immunofluorescence co-localization of CD31 and a-SMA showed that 14 days after moulding, double positive cells for CD31 and a-SMA could be clearly observed in the endometrium."
CD31/alpha-SMA co-localization in the rat injury model; no endothelial lineage tracing quantifies conversion into fibroblasts.
Excessive Endometrial Matrix Deposition partially recapitulates The injury model produces histological fibrosis, with model-specific inflammatory injury.
Limitations: Acute dual injury does not reproduce every human procedure or chronic niche.
Readouts
Histological fibrotic area at day 7
Direction: INCREASED
Interpretation: Masson-stained fibrosis area is increased versus the model control.
Show evidence (1 reference)
PMID:34996477 SUPPORT PRIMARY RESULT Model Organism
"After 7 days, adhesive bands were visible in the uterine cavity, which was reduced or even completely closed, and the area of fibrosis was significantly increased compared with that in the control group."
Actual time-specific histological result in the dual-injury rat model.
Show evidence (1 reference)
PMID:34996477 SUPPORT PRIMARY RESULT Model Organism
"After 7 days, adhesive bands were visible in the uterine cavity, which was reduced or even completely closed, and the area of fibrosis was significantly increased compared with that in the control group."
Actual time-specific histological result in the dual-injury rat model.
The injury can extend into myometrium and models severe acute injury. No endothelial lineage tracing, selective conversion blockade, source fraction or human validation is provided. Marker coexpression cannot establish all fibroblasts as endothelial-derived; sample-size reporting is limited.
Show evidence (2 references)
PMID:34996477 SUPPORT PRIMARY RESULT Model Organism
"To create an infection injury, bacterial lipopolysaccharide (LPS) surgical cotton thread was left in the uterine cavity"
Dual mechanical and inflammatory injury, not a mechanical-only rat model.
PMID:34996477 SUPPORT PRIMARY RESULT Model Organism
"Immunofluorescence co-localization of CD31 and a-SMA showed that 14 days after moulding, double positive cells for CD31 and a-SMA could be clearly observed in the endometrium."
CD31/alpha-SMA co-localization in the rat injury model; no endothelial lineage tracing quantifies conversion into fibroblasts.
Mouse uterine injury with autophagy-pathway drugs
Curettage plus intrauterine LPS produces an IUA-like injury. Chloroquine and rapamycin begin two hours before surgery and continue for two weeks; T3 is administered on days 6–15. Histological fibrosis and epithelial/mesenchymal markers are measured, with four mice per group.
Species
Mouse
Background
Adult eight-week-old female C57BL/6 mice
Publication
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/
Pathograph links
Reduced Epithelial Autophagy perturbs Autophagy-related drugs alter marker readouts in injured uterus.
Limitations: Pharmacological specificity and human flux mediation are unresolved.
Show evidence (1 reference)
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/ SUPPORT PRIMARY RESULT Model Organism
"in an IUA-like mouse model, the autophagy in endometrium was defective accompanied by EEC-EMT, and CQ could inhibit autophagy and aggravate endometrial fibrosis, whereas rapamycin or T3 treatment could improve the autophagic levels and blunt endometrial fibrosis"
Mouse histology and marker findings; prophylactic rapamycin and later T3 differ in timing.
Excessive Endometrial Matrix Deposition partially recapitulates Histological fibrosis is attenuated under the reported rapamycin and T3 schedules.
Readouts
Histological fibrosis after rapamycin or T3
Direction: DECREASED
Interpretation: Histological fibrosis is attenuated under the reported rapamycin and T3 schedules.
Show evidence (1 reference)
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/ SUPPORT PRIMARY RESULT Model Organism
"in an IUA-like mouse model, the autophagy in endometrium was defective accompanied by EEC-EMT, and CQ could inhibit autophagy and aggravate endometrial fibrosis, whereas rapamycin or T3 treatment could improve the autophagic levels and blunt endometrial fibrosis"
Mouse histology and marker findings; prophylactic rapamycin and later T3 differ in timing.
Show evidence (1 reference)
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/ SUPPORT PRIMARY RESULT Model Organism
"in an IUA-like mouse model, the autophagy in endometrium was defective accompanied by EEC-EMT, and CQ could inhibit autophagy and aggravate endometrial fibrosis, whereas rapamycin or T3 treatment could improve the autophagic levels and blunt endometrial fibrosis"
Mouse histology and marker findings; prophylactic rapamycin and later T3 differ in timing.
Notes
Rapamycin is preventive attenuation in this protocol rather than delayed clinical rescue. Chloroquine alone gives a mild nonsignificant fibrosis/EMT trend; injury initiates the model. No pregnancy or live-birth endpoint is measured. The paper inconsistently reports T3 as 40 mg/kg in Methods/Figure 8 and 40 micrograms/kg/day in Discussion; no dose is promoted as a clinical regimen. A mouse DIO2 gene-therapy experiment is not reported.
Show evidence (2 references)
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/ SUPPORT PRIMARY RESULT Model Organism
"in an IUA-like mouse model, the autophagy in endometrium was defective accompanied by EEC-EMT, and CQ could inhibit autophagy and aggravate endometrial fibrosis, whereas rapamycin or T3 treatment could improve the autophagic levels and blunt endometrial fibrosis"
Mouse histology and marker findings; prophylactic rapamycin and later T3 differ in timing.
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/ SUPPORT PRIMARY RESULT Model Organism
"For the pharmacological alteration of autophagy treatment, the mice received CQ (60 mg/kg/d) or rapamycin (2 mg/kg/d) intraperitoneal injection at 2 h prior to surgery and continuously received CQ or rapamycin for 2 weeks."
The dosing schedule establishes prophylactic timing.
Mouse ferroptosis perturbation in uterine injury
The accessible abstract reports mild endometrial EMT/fibrosis after erastin and reduced fibrosis with ferrostatin-1 in a dual-injury IUA model.
Species
Mouse
Publication
PMID:37302615
Pathograph links
Epithelial Ferroptotic Stress perturbs Erastin and ferrostatin-1 perturb a ferroptosis-associated injury model.
Show evidence (1 reference)
PMID:37302615 SUPPORT PRIMARY RESULT Model Organism
"Meanwhile, the ferroptosis inhibitor Fer-1 significantly ameliorated endometrial fibrosis in a dual-injury IUA murine model."
Abstract-limited pharmacological model result, not established human treatment.
Excessive Endometrial Matrix Deposition partially recapitulates Ferrostatin-1 is associated with reduced experimental endometrial fibrosis.
Readouts
Endometrial fibrosis after ferrostatin-1
Direction: DECREASED
Interpretation: Ferrostatin-1 is associated with reduced experimental endometrial fibrosis.
Show evidence (1 reference)
PMID:37302615 SUPPORT PRIMARY RESULT Model Organism
"Meanwhile, the ferroptosis inhibitor Fer-1 significantly ameliorated endometrial fibrosis in a dual-injury IUA murine model."
Abstract-limited pharmacological model result, not established human treatment.
Show evidence (1 reference)
PMID:37302615 SUPPORT PRIMARY RESULT Model Organism
"Meanwhile, the ferroptosis inhibitor Fer-1 significantly ameliorated endometrial fibrosis in a dual-injury IUA murine model."
Abstract-limited pharmacological model result, not established human treatment.
Full experimental methods were unavailable after canonical and primary-publisher retrieval attempts. Strain, dose, intervention timing and group sizes are not inferred. Pharmacological effects do not establish clinical efficacy or exclusive ferroptosis mediation.
Show evidence (1 reference)
PMID:37302615 SUPPORT PRIMARY RESULT Model Organism
"Meanwhile, the ferroptosis inhibitor Fer-1 significantly ameliorated endometrial fibrosis in a dual-injury IUA murine model."
Abstract-limited pharmacological model result, not established human treatment.
{ }

Source YAML

click to show 
name: Asherman_Syndrome
creation_date: '2026-08-22T06:00:00Z'
category: Acquired
disease_term:
  preferred_term: Asherman syndrome
  term:
    id: MONDO:0015299
    label: Asherman syndrome
parents:
- uterine disease
- endometrium disease
classifications:
  harrisons_chapter:
  - classification_value: ENDOCRINOLOGY_METABOLISM
synonyms:
- intrauterine adhesions
- intrauterine synechiae
- uterine synechiae
- Asherman's syndrome
- IUA
description: Asherman syndrome is symptomatic intrauterine or endocervical adhesion disease. Endometrial injury, commonly after pregnancy-related uterine instrumentation and occasionally infection or other uterine procedures, can heal with fibrous tissue and bridging adhesions. Menstrual disturbance, cyclic pain, infertility or pregnancy loss may follow. Residual endometrium and regenerative capacity vary; complete stem-cell depletion is not required or demonstrated in every case. Hysteroscopy defines the cavity lesion and enables adhesiolysis, but recurrence and impaired reproductive outcomes may persist.
notes: Asymptomatic intrauterine adhesions are a related anatomical finding and are not automatically Asherman syndrome. This acquired disorder has no established Mendelian causal gene. Molecular expression changes and experimental perturbations are not inherited pathogenic variants. Clinical scope draws on the AAGL/ESGE guideline and the StatPearls chapter (PMID:28846336; NBK448088), with newer primary studies qualifying adjunct efficacy. The full autophagy paper (PMID:35196191; DOI:10.1080/15548627.2022.2038994) uses its generated PMC URL evidence identity because canonical PMID retrieval remained abstract-only. Human atlas and animal/culture mechanisms are distinguished from established clinical care.
definitions:
- name: Symptomatic intrauterine adhesion disease
  definition_type: DIAGNOSTIC_CRITERIA
  description: Intrauterine or endocervical adhesions accompanied by attributable menstrual disturbance, pain or reproductive dysfunction constitute the symptomatic syndrome; every symptom is not required.
  inclusion_criteria:
  - preferred_term: Intrauterine adhesions established by cavity assessment
  - preferred_term: Attributable pain, menstrual disturbance or subfertility in any combination
  evidence:
  - reference: PMID:28603474
    reference_title: 'AAGL practice report: practice guidelines on intrauterine adhesions developed in collaboration with the European Society of Gynaecological Endoscopy (ESGE).'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: The terms “Asherman syndrome” and IUAs are often used interchangeably, although the syndrome requires the constellation of signs and symptoms (in this case, pain, menstrual disturbance, and subfertility in any combination) related to the presence of IUAs
    explanation: Guideline distinction between an anatomical finding and the symptomatic syndrome.
- name: Hysteroscopic severity classification
  definition_type: OTHER
  description: Document adhesion extent, density, location and residual cavity/endometrium. AFS also incorporates menstrual features; March, ESGE and other schemes use different criteria. Categories describe severity rather than inevitable sequential stages.
  notes: No single system was endorsed as superior in the AAGL/ESGE guideline; outcome associations do not constitute a validated individual live-birth prediction tool.
  evidence:
  - reference: PMID:28603474
    reference_title: 'AAGL practice report: practice guidelines on intrauterine adhesions developed in collaboration with the European Society of Gynaecological Endoscopy (ESGE).'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Intrauterine adhesions should be classified as prognosis is correlated with severity of adhesions. Level B.
    explanation: The guideline supports recording severity.
  - reference: PMID:28603474
    reference_title: 'AAGL practice report: practice guidelines on intrauterine adhesions developed in collaboration with the European Society of Gynaecological Endoscopy (ESGE).'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Consequently, it is currently not possible to endorse any specific system. Level C.
    explanation: Classification systems remain heterogeneous.
phenotypes:
- category: Clinical
  name: Intrauterine adhesions
  description: Fibrous bands bridge portions of the uterine cavity or endocervix; extent and density vary.
  phenotype_term:
    preferred_term: Uterine synechiae
    term:
      id: HP:0030712
      label: Uterine synechiae
  evidence:
  - reference: PMID:37735465
    reference_title: Decoding the endometrial niche of Asherman's Syndrome at single-cell resolution.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Asherman's Syndrome is characterized by intrauterine adhesions or scarring, which cause infertility, menstrual abnormalities, and recurrent pregnancy loss.
    explanation: Clinical review describes this finding; no separate disease-wide frequency is inferred.
    quote_role: REVIEW_SYNTHESIS
  frequency: OBLIGATE
- category: Clinical
  name: Hypomenorrhea
  description: Reduced menstrual flow can reflect loss of functional endometrium or impaired outflow. A combined amenorrhea-or-hypomenorrhea statement does not establish the frequency of either symptom separately.
  phenotype_term:
    preferred_term: Hypomenorrhea
    term:
      id: HP:0000140
      label: Abnormality of the menstrual cycle
    coarse_binding_basis: NO_HPO_TERM
  evidence:
  - reference: PMID:21437822
    reference_title: Asherman's syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Most women with IUA have amenorrhea or hypomenorrhea, but up to a fourth have painless menses of normal flow and duration.
    explanation: Clinical review describes this finding; no separate disease-wide frequency is inferred.
    quote_role: REVIEW_SYNTHESIS
  notes: No exact HPO hypomenorrhea label was found in live OLS search; the menstrual-cycle parent preserves the broader meaning.
- category: Clinical
  name: Amenorrhea
  description: Absent menstruation may reflect impaired endometrial regeneration or outflow obstruction. Normal menstrual flow does not exclude clinically important adhesions.
  phenotype_term:
    preferred_term: Amenorrhea
    term:
      id: HP:0000141
      label: Amenorrhea
  evidence:
  - reference: PMID:21437822
    reference_title: Asherman's syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Most women with IUA have amenorrhea or hypomenorrhea
    explanation: Clinical review describes this finding; no separate disease-wide frequency is inferred.
    quote_role: REVIEW_SYNTHESIS
- category: Clinical
  name: Female infertility
  description: Cavity distortion, tubal-ostial obstruction and impaired endometrial function can contribute to infertility; concurrent tubal, ovarian and partner factors may also matter.
  phenotype_term:
    preferred_term: Female infertility
    term:
      id: HP:0008222
      label: Female infertility
  evidence:
  - reference: PMID:39613882
    reference_title: Mechanistic insights into intrauterine adhesions.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: IUA is a common cause of the refractory uterine infertility.
    explanation: Clinical review describes this finding; no separate disease-wide frequency is inferred.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:21437822
    reference_title: Asherman's syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In addition to abnormal menses, infertility and recurrent spontaneous abortion are common complaints.
    explanation: Clinical review describes this finding; no separate disease-wide frequency is inferred.
    quote_role: REVIEW_SYNTHESIS
- category: Clinical
  name: Recurrent pregnancy loss
  description: Recurrent spontaneous pregnancy loss is a recognized presentation. Post-treatment pregnancy-loss rates do not estimate its frequency among all untreated patients.
  phenotype_term:
    preferred_term: Recurrent spontaneous abortion
  evidence:
  - reference: PMID:21437822
    reference_title: Asherman's syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In addition to abnormal menses, infertility and recurrent spontaneous abortion are common complaints.
    explanation: Clinical review describes this finding; no separate disease-wide frequency is inferred.
    quote_role: REVIEW_SYNTHESIS
  notes: HP:0200067 Recurrent spontaneous abortion is outside the phenotypic-abnormality root used by the current dynamic enum; an unrelated fetal phenotype is not substituted.
- category: Clinical
  name: Cyclic pelvic pain
  description: Obstructed menstrual flow can cause recurrent pelvic pain, particularly in patients with amenorrhea and residual cycling endometrium.
  phenotype_term:
    preferred_term: Pelvic pain
    term:
      id: HP:0034267
      label: Pelvic pain
    temporality: RECURRENT
  evidence:
  - reference: PMID:21437822
    reference_title: Asherman's syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Those who have amenorrhea may also have cyclic pelvic pain caused by outflow obstruction.
    explanation: Clinical review describes this finding; no separate disease-wide frequency is inferred.
    quote_role: REVIEW_SYNTHESIS
- category: Clinical
  name: Secondary endometriosis
  description: Retrograde menstruation accompanying outflow obstruction is a proposed possible route to coexisting endometriosis, not an inevitable consequence or established population risk.
  phenotype_term:
    preferred_term: Endometriosis
    term:
      id: HP:0030127
      label: Endometriosis
  evidence:
  - reference: PMID:21437822
    reference_title: Asherman's syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The accompanying retrograde menstruation may lead to endometriosis.
    explanation: Clinical review describes this finding; no separate disease-wide frequency is inferred.
    quote_role: REVIEW_SYNTHESIS
- name: Hematometra
  category: Clinical
  description: Retained menstrual blood may occur with obstructing adhesions and contribute to cyclic pain. It is not present in every patient.
  phenotype_term:
    preferred_term: Hematometra
  notes: No exact hematometra HPO term was found in live OLS search.
  evidence:
  - reference: PMID:28603474
    reference_title: 'AAGL practice report: practice guidelines on intrauterine adhesions developed in collaboration with the European Society of Gynaecological Endoscopy (ESGE).'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: treatment should be considered only when there are signs or symptoms of pain, infertility, recurrent pregnancy loss, or menstrual abnormalities including hematometra.
    explanation: Guideline identifies retained menstrual blood among clinically relevant presentations.
- name: Placenta accreta
  category: Clinical
  description: Abnormally adherent placentation is a risk in pregnancies after intrauterine adhesion disease and its treatment. Estimates depend on the selected pregnancy cohort and do not describe all affected patients.
  phenotype_term:
    preferred_term: Placenta accreta
    term:
      id: HP:0025654
      label: Placenta accreta
  evidence:
  - reference: PMID:30713131
    reference_title: 'Reproductive outcomes after surgical treatment of asherman syndrome: A systematic review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: 'placenta accreta syndrome was 10.1% (95% CI: 8.6 to 11.8) in 23 studies'
    explanation: A pooled post-adhesiolysis pregnancy complication, not an untreated disease frequency.
prevalence:
- population: Women evaluated by hysteroscopy within 12 months of a miscarriage
  measure_type: PERIOD_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 19100.0
  rate_low: 12800.0
  rate_high: 27500.0
  notes: The 2014 review included 912 women in ten prospective studies evaluated by hysteroscopy within twelve months of miscarriage after spontaneous expulsion or medical/surgical management. There were 183 detected adhesions; the pooled prevalence was 19.1% (95% CI 12.8–27.5%). Severity was reported for 124, of whom 58.1% had mild adhesions. This is selected post-miscarriage IUA prevalence, including findings of uncertain clinical importance, not general-population prevalence of symptomatic Asherman syndrome.
  evidence:
  - reference: PMID:24082042
    reference_title: 'Systematic review and meta-analysis of intrauterine adhesions after miscarriage: prevalence, risk factors and long-term reproductive outcome.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'IUAs were detected in 183 women, resulting in a pooled prevalence of 19.1% [95% confidence interval (CI): 12.8-27.5%].'
    explanation: The pooled point estimate and interval recorded in this record.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:24082042
    reference_title: 'Systematic review and meta-analysis of intrauterine adhesions after miscarriage: prevalence, risk factors and long-term reproductive outcome.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In more than half of these, the severity and extent of the adhesions was mild, with unknown clinical relevance.
    explanation: 'Deliberate limit on the number above: the pooled figure counts hysteroscopic lesions, most of them mild, and must not be read as the prevalence of symptomatic Asherman syndrome.'
    quote_role: REVIEW_SYNTHESIS
epidemiology:
- name: Repeated uterine instrumentation
  description: Repeated miscarriage and dilation/curettage are associated with adhesion detection. The number of curettages may contribute, but pre-existing uterine conditions and indications for repeated treatment complicate causal attribution.
  evidence:
  - reference: PMID:24082042
    reference_title: 'Systematic review and meta-analysis of intrauterine adhesions after miscarriage: prevalence, risk factors and long-term reproductive outcome.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: The number of dilatation and curettage (D&C) procedures seemed to be the main driver behind these associations.
    explanation: The systematic review qualifies the proposed mediator.
- name: Pregnancy-related injury context
  description: Pregnancy-related and postpartum uterine procedures account for many reported cases. These case distributions are not procedure-specific risks, and nonpregnant uterine surgery can also precede adhesions.
  evidence:
  - reference: PMID:21437822
    reference_title: Asherman's syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Although it usually occurs following curettage of the pregnant or recently pregnant uterus, any uterine surgery can lead to intrauterine adhesions (IUA).
    explanation: Clinical review preserves the broader procedural spectrum.
- name: Genital tuberculosis
  description: Genital tuberculosis can injure the endometrium and cause adhesions, often alongside tubal disease. Consider exposure and regional context when clinically indicated; tuberculosis is not the cause of most post-instrumentation cases.
  evidence:
  - reference: PMID:31388435
    reference_title: Case report of pelvic tuberculosis resulting in Asherman's syndrome and infertility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: We present a case of genital tuberculosis causing Asherman's syndrome and resultant infertility.
    explanation: One infection-associated case report; no population rate is inferred.
diagnosis:
- name: Hysteroscopy
  description: Direct visualization is the diagnostic reference standard when the cavity is accessible. Record location, extent, density and residual endometrium; it can permit concurrent adhesiolysis. Severe obliteration requires specialist assessment.
  diagnosis_term:
    preferred_term: Hysteroscopy
    term:
      id: NCIT:C148437
      label: Hysteroscopy
  evidence:
  - reference: PMID:28603474
    reference_title: 'AAGL practice report: practice guidelines on intrauterine adhesions developed in collaboration with the European Society of Gynaecological Endoscopy (ESGE).'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Hysteroscopy is the most accurate method for diagnosis of IUAs and should be the investigation of choice when available. Level B.
    explanation: AAGL/ESGE recommendation.
- name: Contrast cavity imaging
  description: Saline/gel infusion sonography or hysterosalpingography may assess the cavity when hysteroscopy is unavailable or during initial evaluation. HSG also assesses tubal patency. False-positive and false-negative findings limit replacement of hysteroscopy.
  evidence:
  - reference: PMID:28603474
    reference_title: 'AAGL practice report: practice guidelines on intrauterine adhesions developed in collaboration with the European Society of Gynaecological Endoscopy (ESGE).'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: If hysteroscopy is not available, HSG and SHG are reasonable alternatives. Level B.
    explanation: Alternative cavity assessment with imperfect accuracy.
- name: Selective MRI in an inaccessible cavity
  description: MRI is not a routine diagnostic requirement. The 2017 guideline restricts it to research, while the 2019 review describes possible value in rare totally obstructed cavities where standard cavity tests are limited; selection is specialist-dependent.
  evidence:
  - reference: PMID:28603474
    reference_title: 'AAGL practice report: practice guidelines on intrauterine adhesions developed in collaboration with the European Society of Gynaecological Endoscopy (ESGE).'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Magnetic resonance imaging should not be used for diagnosis of IUAs outside of clinical research studies. Level C.
    explanation: Guideline restriction.
  - reference: PMID:30936754
    reference_title: 'Asherman''s syndrome: current perspectives on diagnosis and management.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: In these rare cases MRI can be valuable, although too expensive as a routine diagnostic tool.
    explanation: Later review discusses selective use after total obstruction.
- name: Amenorrhea and fertility evaluation
  description: Evaluate pregnancy and endocrine causes of amenorrhea and other contributors to infertility. Failure to bleed after an estrogen-progesterone challenge with otherwise intact ovarian-axis function supports an outflow/endometrial cause but is not itself definitive proof of adhesions.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK448088/
    reference_title: Asherman Syndrome - StatPearls - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: The failure to induce menses despite stimulating the endometrium with an estrogen-progesterone challenge, in a patient with secondary amenorrhea, with normal hypothalamic-pituitary-ovarian functions and hormone levels, points towards the diagnosis of Asherman's syndrome.
    explanation: Clinical differential assessment.
- name: Endometrial testing for suspected genital tuberculosis
  description: When exposure and clinical findings suggest infection, endometrial histology, acid-fast staining and mycobacterial culture can support the diagnosis. A negative chest radiograph does not exclude genital tuberculosis.
  evidence:
  - reference: PMID:31388435
    reference_title: Case report of pelvic tuberculosis resulting in Asherman's syndrome and infertility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: necrotizing granulomas with acid- fast bacilli positive and culture positive for Mycobac- terium tuberculosis
    explanation: Confirmed infection in a selected patient, not universal screening or assay sensitivity.
progression:
- phase: Recurrence after adhesiolysis
  notes: Adhesions may recur after technically successful cavity restoration. More extensive baseline disease generally requires more treatment; an open cavity does not guarantee recovered endometrial function or fertility.
  evidence:
  - reference: PMID:28603474
    reference_title: 'AAGL practice report: practice guidelines on intrauterine adhesions developed in collaboration with the European Society of Gynaecological Endoscopy (ESGE).'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: recurrence is common and may occur in 30 to 66% of women treated for IUAs
    explanation: A guideline range from selected treated cohorts rather than a fixed patient prognosis.
- phase: Reproductive outcomes after adhesiolysis
  notes: A 2019 systematic review of 54 studies and 4,640 women of varying quality pooled pregnancy at 50.7% across 53 studies. Early loss, mid-trimester loss, ectopic pregnancy, cervical incompetence and abnormal placentation were reported in different subsets. These outcomes cannot be summed or treated as one longitudinal sequence or as frequencies in untreated disease. Residual severity, other fertility factors, follow-up and treatment protocols differ.
  evidence:
  - reference: PMID:30713131
    reference_title: 'Reproductive outcomes after surgical treatment of asherman syndrome: A systematic review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: There were 54 studies (4640 women) of varying quality.
    explanation: Heterogeneous treated-study base.
  - reference: PMID:30713131
    reference_title: 'Reproductive outcomes after surgical treatment of asherman syndrome: A systematic review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: The pooled rate of pregnancy was 50.7%
    explanation: Post-treatment pooled pregnancy proportion.
  - reference: PMID:30713131
    reference_title: 'Reproductive outcomes after surgical treatment of asherman syndrome: A systematic review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: 'early pregnancy loss was 17.7% (95% CI: 15.9 to 19.6) in 31 studies, ectopic pregnancy (EP) was 4.2% (95% CI: 2.8 to 6.3) in 9 studies, mid-trimester loss (MTL) was 11.5% (95% CI: 7.6 to 17.8) in 7 studies, cervical incompetence was 12.5% (95% CI: 3.3 to 33.5) in 2 studies and placenta accreta syndrome was 10.1% (95% CI: 8.6 to 11.8) in 23 studies'
    explanation: Each complication uses a distinct study subset; no disease-wide phenotype band is inferred.
differential_diagnoses:
- name: Endocrine or ovarian causes of amenorrhea
  description: Pregnancy, thyroid, hypothalamic/pituitary and ovarian dysfunction require assessment; ovarian-axis tests and cavity evaluation distinguish overlapping presentations.
  distinguishing_features:
  - Endocrine abnormalities or pregnancy without a required adhesion lesion
- name: Isolated cervical stenosis
  description: An outflow lesion may cause amenorrhea or cyclic pain without endometrial bridging adhesions throughout the cavity.
  distinguishing_features:
  - Localized cervical obstruction with an otherwise preserved cavity
- name: Endometriosis or adenomyosis
  description: These can cause pain and infertility and may coexist with adhesion disease. They do not require intrauterine synechiae; a patent cavity does not exclude either condition.
  distinguishing_features:
  - Endometriotic lesions outside the cavity or endometrial-type tissue within myometrium
treatments:
- name: Hysteroscopic adhesiolysis
  description: Direct-vision division of symptomatic adhesions is the standard lesion-directed approach (AAGL/ESGE Level B). Severe or extensive disease warrants experienced hysteroscopic care. Cold scissors avoid thermal injury, but randomized evidence does not establish superiority of one instrument. Blind curettage and blind probing are not supported. Image guidance may help selected difficult procedures without demonstrated prevention of perforation.
  treatment_term:
    preferred_term: Hysteroscopy
    term:
      id: NCIT:C148437
      label: Hysteroscopy
  target_mechanisms:
  - target: Intrauterine Adhesion Formation
    treatment_effect: INHIBITS
    description: Division of existing bridging adhesions restores cavity access; it does not assure recovered endometrial function or fertility.
    evidence:
    - reference: PMID:28603474
      reference_title: 'AAGL practice report: practice guidelines on intrauterine adhesions developed in collaboration with the European Society of Gynaecological Endoscopy (ESGE).'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: Hysteroscopic lysis of adhesions by direct vision and a tool for adhesiolysis is the recommended approach for symptomatic IUAs. Level B
      explanation: Recommended lesion-directed treatment for symptomatic disease.
  evidence:
  - reference: PMID:28603474
    reference_title: 'AAGL practice report: practice guidelines on intrauterine adhesions developed in collaboration with the European Society of Gynaecological Endoscopy (ESGE).'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Hysteroscopic lysis of adhesions by direct vision and a tool for adhesiolysis is the recommended approach for symptomatic IUAs. Level B
    explanation: Recommended lesion-directed treatment for symptomatic disease.
  - reference: PMID:28603474
    reference_title: 'AAGL practice report: practice guidelines on intrauterine adhesions developed in collaboration with the European Society of Gynaecological Endoscopy (ESGE).'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: There is no evidence to support the use of blind dilation and curettage. Level C.
    explanation: Avoid replacing visual treatment with blind curettage.
- name: Temporary intrauterine physical barriers
  description: An inert large-surface-area IUD, balloon, stent or catheter may separate healing surfaces after adhesiolysis. The guideline grades reduced reformation A but notes limited subsequent fertility data; device and duration depend on clinical context. Copper-containing and progestin-containing IUDs should not be substituted for the recommended inert device.
  target_mechanisms:
  - target: Intrauterine Adhesion Formation
    treatment_effect: INHIBITS
    description: Temporary separation aims to reduce postoperative adhesion reformation.
    evidence:
    - reference: PMID:28603474
      reference_title: 'AAGL practice report: practice guidelines on intrauterine adhesions developed in collaboration with the European Society of Gynaecological Endoscopy (ESGE).'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: The use of an IUD, stent, or catheter appears to reduce the rate of postoperative adhesion reformation. There are limited data regarding subsequent fertility outcomes when these barriers are used. Grade A
      explanation: Recurrence and fertility are distinct outcomes.
  evidence:
  - reference: PMID:28603474
    reference_title: 'AAGL practice report: practice guidelines on intrauterine adhesions developed in collaboration with the European Society of Gynaecological Endoscopy (ESGE).'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: The use of an IUD, stent, or catheter appears to reduce the rate of postoperative adhesion reformation. There are limited data regarding subsequent fertility outcomes when these barriers are used. Grade A
    explanation: Recurrence and fertility are distinct outcomes.
  - reference: PMID:28603474
    reference_title: 'AAGL practice report: practice guidelines on intrauterine adhesions developed in collaboration with the European Society of Gynaecological Endoscopy (ESGE).'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: If an IUD is used postoperatively, it should be inert and have a large surface area such as a Lippes loop. Intrauterine devices that contain progestin or copper should not be used after surgical division of IUAs. Grade C
    explanation: Device-specific limitation.
- name: Hyaluronic-acid adhesion barriers
  description: Selected postoperative semi-solid barriers can reduce adhesion reformation, but the size of benefit and reproductive outcomes vary by product, procedure and comparator. A network meta-analysis of 21 randomized trials and 2,406 patients did not establish a significant clinical-pregnancy advantage across the compared adjuvants; ranking changes in adhesion scores is not a live-birth recommendation.
  treatment_term:
    preferred_term: Hyaluronic-acid adhesion barrier
    therapeutic_agent:
    - preferred_term: hyaluronic acid
      term:
        id: CHEBI:16336
        label: hyaluronic acid
  target_mechanisms:
  - target: Intrauterine Adhesion Formation
    treatment_effect: INHIBITS
    description: Barrier-associated reduction in reformation does not prove regeneration of receptive endometrium.
    evidence:
    - reference: PMID:28603474
      reference_title: 'AAGL practice report: practice guidelines on intrauterine adhesions developed in collaboration with the European Society of Gynaecological Endoscopy (ESGE).'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: Semi-solid barriers such as hyaluronic acid and auto-cross-linked hyaluronic acid gel reduce adhesion reformation. At this time, their effect on post-treatment pregnancy rates is unknown. Grade A
      explanation: The 2017 recommendation concerns adhesion reformation rather than established live-birth benefit.
  evidence:
  - reference: PMID:28603474
    reference_title: 'AAGL practice report: practice guidelines on intrauterine adhesions developed in collaboration with the European Society of Gynaecological Endoscopy (ESGE).'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Semi-solid barriers such as hyaluronic acid and auto-cross-linked hyaluronic acid gel reduce adhesion reformation. At this time, their effect on post-treatment pregnancy rates is unknown. Grade A
    explanation: The 2017 recommendation concerns adhesion reformation rather than established live-birth benefit.
  - reference: PMID:38493418
    reference_title: 'Intrauterine interventions options for preventing recurrence after hysteroscopic adhesiolysis: a systematic review and network meta-analysis of randomized controlled trials.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: 21 randomized controlled trials involving 2406 patients
    explanation: Network review population; heterogeneous adjuncts and endpoints.
- name: Postoperative estrogen with or without progestin
  description: The 2017 guideline gives a Grade B recommendation that estrogen may reduce recurrence. A later single-centre randomized trial found no significant adhesion, pregnancy or living-child benefit from adding estrogen in selected women with previously regular ovulatory cycles, successful adhesiolysis and an inert IUD in both groups. Of 114 analyzed women, second-look recurrence was 16/59 versus 14/55; living-child outcomes were 40/59 versus 33/55. Wide uncertainty, selection and the shared barrier limit extrapolation to every regimen or anovulatory patient. Side effects were frequent in the estrogen group. These results do not demonstrate equivalence or a universal regenerative effect.
  evidence:
  - reference: PMID:28603474
    reference_title: 'AAGL practice report: practice guidelines on intrauterine adhesions developed in collaboration with the European Society of Gynaecological Endoscopy (ESGE).'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Following hysteroscopic-directed adhesiolysis, postoperative hormone treatment using estrogen, with or without progestin, may reduce recurrence of IUAs. Grade B
    explanation: Older conditional recommendation.
  - reference: PMID:37396823
    reference_title: 'Hormonal support in women with Asherman syndrome does not lead to better outcomes: A randomized trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Of the women in usual care, 89.8% got pregnant within 3 years, and 67.8% got a living child; this was 83.6% and 60.0%, respectively, in the no-estrogen group (p = 0.33 and p = 0.39, respectively).
    explanation: Trial endpoints are nonsignificant, not proof of general equivalence.
- name: Post-treatment cavity reassessment
  description: Reassess the uterine cavity, preferably hysteroscopically (Grade B), because recurrence may require further treatment. Timing is individualized; the guideline discusses reassessment after two to three cycles and earlier second-look approaches. Surveillance identifies recurrence rather than independently restoring endometrial function.
  evidence:
  - reference: PMID:28603474
    reference_title: 'AAGL practice report: practice guidelines on intrauterine adhesions developed in collaboration with the European Society of Gynaecological Endoscopy (ESGE).'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Follow-up assessment of the uterine cavity after treatment of IUAs is recommended, preferably with hysteroscopy. Grade B
    explanation: Recommended follow-up after treatment.
- name: Pregnancy and fertility follow-up
  description: Evaluate other infertility factors when conception does not follow cavity restoration. Subsequent pregnancies warrant attention to abnormal placentation, pregnancy loss, prematurity and retained placenta. Post-adhesiolysis cohort risks do not establish a fixed outcome for an individual pregnancy.
  evidence:
  - reference: PMID:30713131
    reference_title: 'Reproductive outcomes after surgical treatment of asherman syndrome: A systematic review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: 'placenta accreta syndrome was 10.1% (95% CI: 8.6 to 11.8) in 23 studies'
    explanation: Selected treated-pregnancy evidence supports attention to placentation; it does not test a particular surveillance protocol.
- name: Treatment of confirmed genital tuberculosis
  description: Treat confirmed genital tuberculosis with appropriate multidrug antimicrobial care and infectious-disease input; adhesions and infertility may persist after microbiological treatment. One reported patient received two months of rifampin, isoniazid, pyrazinamide and ethambutol, followed by rifampin/isoniazid, with an extension after persistent acid-fast staining despite negative culture. Cyclic spotting returned only during subsequent estrogen priming; neither antibiotic-only menstrual recovery nor restored fertility was demonstrated.
  treatment_term:
    preferred_term: Antituberculous pharmacotherapy
    therapeutic_agent:
    - preferred_term: rifampicin
      term:
        id: CHEBI:28077
        label: rifampicin
    - preferred_term: isoniazide
      term:
        id: CHEBI:6030
        label: isoniazide
    - preferred_term: pyrazinamide
      term:
        id: CHEBI:45285
        label: pyrazinecarboxamide
    - preferred_term: ethambutol
      term:
        id: CHEBI:4877
        label: ethambutol
  evidence:
  - reference: PMID:31388435
    reference_title: Case report of pelvic tuberculosis resulting in Asherman's syndrome and infertility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: At this time, the patient was started on 2-month course of 4-drug Rifampin, Isoniazid, Pyrazinamide, and Ethambutol (RIPE) therapy followed by 4 months of ri- fampin and isoniazid.
    explanation: Actual reported regimen; individual management is not a universally validated AS treatment protocol.
- name: No routine perioperative antibiotic recommendation
  description: The AAGL/ESGE guideline finds insufficient evidence for or against antibiotics specifically to prevent postoperative adhesions. This uncertainty does not replace treatment of a documented infection or other independently indicated prophylaxis.
  evidence:
  - reference: PMID:28603474
    reference_title: 'AAGL practice report: practice guidelines on intrauterine adhesions developed in collaboration with the European Society of Gynaecological Endoscopy (ESGE).'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: There is no evidence to support or refute the use of preoperative, intraoperative, or postoperative antibiotic therapy in surgical treatment of IUAs. Grade C
    explanation: No established adhesion-prevention benefit.
- name: Investigational regenerative and molecular therapies
  description: Stem-cell approaches and agents intended to alter vascular flow remain research interventions. Animal T3, rapamycin and ferrostatin findings do not establish human fertility benefit or a clinical regimen. Putative stem-cell benefit may involve niche/paracrine changes rather than durable replacement of all missing epithelial progenitors; controlled clinical efficacy remains a separate question.
  evidence:
  - reference: PMID:28603474
    reference_title: 'AAGL practice report: practice guidelines on intrauterine adhesions developed in collaboration with the European Society of Gynaecological Endoscopy (ESGE).'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Stem cell treatment may ultimately provide an effective adjuvant approach to the treatment of Asherman syndrome; however, evidence is very limited and this treatment should not be offered outside of rigorous research protocols. Grade C
    explanation: Research-only status in the guideline.
  - reference: PMID:28603474
    reference_title: 'AAGL practice report: practice guidelines on intrauterine adhesions developed in collaboration with the European Society of Gynaecological Endoscopy (ESGE).'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: The role of medications designed as adjuvants to improve vascular flow to the endometrium has not been established. Consequently, they should not be used outside of rigorous research protocols. Grade C
    explanation: No established vascular adjunct regimen.
clinical_trials:
- name: NCT05394662
  phase: PHASE_III
  status: COMPLETED
  description: Juveena Hydrogel barrier trial after adhesiolysis or myomectomy. The 2026 report randomized 150 participants (99 hydrogel, 51 control), including 102 undergoing adhesiolysis. In that subgroup, 60.3% versus 32.3% were adhesion-free at second look (OR 3.19, 95% CI 1.29–7.90). The mixed-procedure study and short-term hysteroscopic endpoint do not establish live-birth efficacy; reported device-safety follow-up extended through three weeks. The abstract does not establish that this product is interchangeable with all hyaluronic-acid barriers.
  notes: 'Live ClinicalTrials.gov API checked on 2026-09-21: completed, phase 3 as explicitly registered; actual completion 2025-04-23. Registry and published report are distinguished from guideline endorsement.'
  evidence:
  - reference: clinicaltrials:NCT05394662
    reference_title: 'Safety and Effectiveness of Juveena™ Hydrogel System Following Transcervical Gynecologic Procedures (TCGP) At High-Risk for Intrauterine Adhesions: A Multicenter Randomized Controlled Subject and Evaluator Blinded Pivotal Study'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: PRIMARY_RESULT
    snippet: This study is to determine whether intrauterine instillation of Juveena hydrogel following adhesiogenic hysteroscopic procedures (TCGP + Juveena) can safely and effectively reduce the incidence and severity of intrauterine adhesions (IUA) compared to TCGP alone.
    explanation: Registry identity/design; status and phase verified separately through the live API on 2026-09-21.
  - reference: PMID:42492609
    reference_title: 'Safety and effectiveness of an in situ-forming hydrogel barrier in preventing intrauterine adhesions after adhesiogenic hysteroscopic procedures: a multicenter, randomized, controlled trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: 'Between August 2022 and January 2025, 150 participants were randomized (hydrogel barrier: n = 99; control: n = 51).'
    explanation: Published randomized study denominator.
  - reference: PMID:42492609
    reference_title: 'Safety and effectiveness of an in situ-forming hydrogel barrier in preventing intrauterine adhesions after adhesiogenic hysteroscopic procedures: a multicenter, randomized, controlled trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: 'In the adhesiolysis subgroup (n = 102), more participants in the hydrogel barrier arm were adhesion-free compared with controls (60.3% vs. 32.3%; odds ratio [OR] 3.19, 95% confidence interval [CI]: 1.29-7.90)'
    explanation: Selected subgroup with anatomical outcome and uncertainty.
pathophysiology:
- name: Endometrial Basal Layer Injury
  biological_scale: TISSUE
  description: Pregnancy-related instrumentation, other uterine procedures or genital infection can damage the regenerative endometrial compartment. Injury context and residual tissue vary; this is not proof that every progenitor is eliminated.
  evidence:
  - reference: PMID:30936754
    reference_title: 'Asherman''s syndrome: current perspectives on diagnosis and management.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Intrauterine adhesions can develop from lesion of the basal layer of the endometrium caused by curettage of the newly pregnant uterus. The syndrome may also occur after hysteroscopic surgery, uterine artery embolization or uterine tuberculosis.
    explanation: Names the basal-layer lesion as the origin and enumerates the four routes to it that this node covers.
  locations:
  - preferred_term: basal layer of endometrium
    term:
      id: UBERON:0022355
      label: basal layer of endometrium
  - preferred_term: uterus
    term:
      id: UBERON:0000995
      label: uterus
  conforms_to: fibrotic_response#Tissue Injury
  downstream:
  - target: Inflammatory Endometrial Niche
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Injury may establish an inflammatory repair environment; human atlas timing does not prove that the measured niche precedes adhesion formation.
    evidence:
    - reference: PMID:30936754
      reference_title: 'Asherman''s syndrome: current perspectives on diagnosis and management.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Intrauterine adhesions can develop from lesion of the basal layer of the endometrium caused by curettage of the newly pregnant uterus. The syndrome may also occur after hysteroscopic surgery, uterine artery embolization or uterine tuberculosis.
      explanation: Names the basal-layer lesion as the origin and enumerates the four routes to it that this node covers.
      directness: INDIRECT
    - reference: PMID:37735465
      reference_title: Decoding the endometrial niche of Asherman's Syndrome at single-cell resolution.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: We describe syndrome-associated alterations in cell-to-cell communication and gene expression profiles that support a dysfunctional pro-fibrotic, pro-inflammatory, and anti-angiogenic environment.
      explanation: Cross-sectional transcriptional and inferred ligand-receptor context, without direct cytokine secretion or angiogenesis assays.
      directness: INDIRECT
  - target: Reduced Endometrial Epithelial Abundance
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Injury can reduce epithelial coverage, but the human atlas does not trace the time course or prove universal stem-cell depletion.
    evidence:
    - reference: PMID:30936754
      reference_title: 'Asherman''s syndrome: current perspectives on diagnosis and management.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Intrauterine adhesions can develop from lesion of the basal layer of the endometrium caused by curettage of the newly pregnant uterus. The syndrome may also occur after hysteroscopic surgery, uterine artery embolization or uterine tuberculosis.
      explanation: Names the basal-layer lesion as the origin and enumerates the four routes to it that this node covers.
      directness: INDIRECT
    - reference: PMID:37735465
      reference_title: Decoding the endometrial niche of Asherman's Syndrome at single-cell resolution.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Our endometrial atlas highlights the loss of the endometrial epithelium, alterations to epithelial differentiation signaling pathways such as Wnt and Notch, and the appearance of characteristic epithelium expressing secretory leukocyte protease inhibitor during the window of implantation.
      explanation: Human recovered-cell and transcriptional observations; cell proportions are not stereological tissue-volume measurements.
      directness: INDIRECT
  - target: Excessive Endometrial Matrix Deposition
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Some injuries heal with scar rather than complete regeneration; multiple cellular intermediates remain unresolved.
    evidence:
    - reference: PMID:30936754
      reference_title: 'Asherman''s syndrome: current perspectives on diagnosis and management.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Intrauterine adhesions can develop from lesion of the basal layer of the endometrium caused by curettage of the newly pregnant uterus. The syndrome may also occur after hysteroscopic surgery, uterine artery embolization or uterine tuberculosis.
      explanation: Names the basal-layer lesion as the origin and enumerates the four routes to it that this node covers.
      directness: INDIRECT
    - reference: PMID:39613882
      reference_title: Mechanistic insights into intrauterine adhesions.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: This damage leads to nonregenerative healing of endometrium resulting in replacement by fibrous connective tissue
      explanation: States the replacement of endometrium by fibrous connective tissue that this node asserts.
      directness: INDIRECT
- name: Inflammatory Endometrial Niche
  biological_scale: TISSUE
  description: Selected human AS biopsies show altered immune-cell proportions and inflammatory expression/communication signatures. These observations do not directly measure cytokine secretion, immune recruitment rates or angiogenic capacity, and active endometritis was excluded from the atlas.
  evidence:
  - reference: PMID:37735465
    reference_title: Decoding the endometrial niche of Asherman's Syndrome at single-cell resolution.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: We describe syndrome-associated alterations in cell-to-cell communication and gene expression profiles that support a dysfunctional pro-fibrotic, pro-inflammatory, and anti-angiogenic environment.
    explanation: Cross-sectional transcriptional and inferred ligand-receptor context, without direct cytokine secretion or angiogenesis assays.
  locations:
  - preferred_term: endometrium
    term:
      id: UBERON:0001295
      label: endometrium
  downstream:
  - target: Stromal Fibrogenic Activation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: An inflammatory niche may favor a fibrogenic stromal state; the cross-sectional atlas does not establish a specific cytokine as necessary.
    evidence:
    - reference: PMID:37735465
      reference_title: Decoding the endometrial niche of Asherman's Syndrome at single-cell resolution.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: We describe syndrome-associated alterations in cell-to-cell communication and gene expression profiles that support a dysfunctional pro-fibrotic, pro-inflammatory, and anti-angiogenic environment.
      explanation: Cross-sectional transcriptional and inferred ligand-receptor context, without direct cytokine secretion or angiogenesis assays.
      directness: INDIRECT
- name: Reduced Endometrial Epithelial Abundance
  biological_scale: CELLULAR
  description: The human single-cell atlas recovered a lower epithelial proportion from sampled AS endometrium. Dissociation, selection, hormonal treatment and clinical severity constrain interpretation; neither absolute tissue cell counts nor elimination of every stem/progenitor population was demonstrated.
  evidence:
  - reference: PMID:37735465
    reference_title: Decoding the endometrial niche of Asherman's Syndrome at single-cell resolution.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Our endometrial atlas highlights the loss of the endometrial epithelium, alterations to epithelial differentiation signaling pathways such as Wnt and Notch, and the appearance of characteristic epithelium expressing secretory leukocyte protease inhibitor during the window of implantation.
    explanation: Human recovered-cell and transcriptional observations; cell proportions are not stereological tissue-volume measurements.
  cell_types:
  - preferred_term: endometrial epithelial cell
    term:
      id: CL:0002149
      label: epithelial cell of uterus
  locations:
  - preferred_term: endometrium
    term:
      id: UBERON:0001295
      label: endometrium
  downstream:
  - target: Reduced Receptive Endometrial Surface
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reduced epithelial coverage may limit the functional implantation surface; cell abundance and clinical receptivity were not experimentally separated.
    evidence:
    - reference: PMID:37735465
      reference_title: Decoding the endometrial niche of Asherman's Syndrome at single-cell resolution.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Our endometrial atlas highlights the loss of the endometrial epithelium, alterations to epithelial differentiation signaling pathways such as Wnt and Notch, and the appearance of characteristic epithelium expressing secretory leukocyte protease inhibitor during the window of implantation.
      explanation: Human recovered-cell and transcriptional observations; cell proportions are not stereological tissue-volume measurements.
      directness: INDIRECT
    - reference: PMID:30713131
      reference_title: 'Reproductive outcomes after surgical treatment of asherman syndrome: A systematic review.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: The pregnancy rate in women with severe adhesion was significantly lower than that in women with mild adhesion (P = 0.021).
      explanation: Selected post-adhesiolysis study synthesis supports a burden-outcome association, not an isolated assay of receptivity.
      directness: INDIRECT
  - target: Hypomenorrhea
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Loss of functioning endometrial surface may reduce menstrual shedding, independently of obstruction.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK448088/
      reference_title: Asherman Syndrome - StatPearls - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Patients with Asherman syndrome may have light or absent menstrual periods (amenorrhea). Still, some patients have normal periods based on the surface area of the cavity that is affected.
      explanation: Clinical review relates menstrual expression to affected surface area; no universal symptom frequency follows.
      directness: INDIRECT
  - target: Amenorrhea
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Severe loss of functioning endometrium may prevent menstrual shedding; endocrine and outflow causes require separate assessment.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK448088/
      reference_title: Asherman Syndrome - StatPearls - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Patients with Asherman syndrome may have light or absent menstrual periods (amenorrhea). Still, some patients have normal periods based on the surface area of the cavity that is affected.
      explanation: Clinical review relates menstrual expression to affected surface area; no universal symptom frequency follows.
      directness: INDIRECT
- name: Reduced WNT Communication Signature
  biological_scale: MOLECULAR
  description: CellChat inferred reduced selected canonical and noncanonical WNT ligand-receptor interactions during the window of implantation. This is expression-based inference from selected human tissue, not direct pathway-activity measurement or a proven primary defect.
  evidence:
  - reference: PMID:37735465
    reference_title: Decoding the endometrial niche of Asherman's Syndrome at single-cell resolution.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: specific absence of WNT7A-FZD6/LRP6 interactions in SOX9-epithelial cells and WNT5A-FZD6 interaction between stromal and luminal cell subtypes in AS
    explanation: Computational communication inference from human single-cell data.
  biological_processes:
  - preferred_term: Wnt signaling pathway
    term:
      id: GO:0016055
      label: Wnt signaling pathway
    modifier: DYSREGULATED
  downstream:
  - target: Reduced Receptive Endometrial Surface
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Altered WNT communication may contribute to impaired epithelial differentiation and receptivity; composition, hormone exposure and causality are unresolved.
    evidence:
    - reference: PMID:37735465
      reference_title: Decoding the endometrial niche of Asherman's Syndrome at single-cell resolution.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Our endometrial atlas highlights the loss of the endometrial epithelium, alterations to epithelial differentiation signaling pathways such as Wnt and Notch, and the appearance of characteristic epithelium expressing secretory leukocyte protease inhibitor during the window of implantation.
      explanation: Human recovered-cell and transcriptional observations; cell proportions are not stereological tissue-volume measurements.
      directness: INDIRECT
    hypothesis_groups:
    - niche_dysfunction
- name: Reduced NOTCH Communication Signature
  biological_scale: MOLECULAR
  description: The atlas inferred reduced JAG1-NOTCH2-associated communication in glandular and luminal populations. Receptor activation, lineage transition and pathway-specific rescue were not tested.
  evidence:
  - reference: PMID:37735465
    reference_title: Decoding the endometrial niche of Asherman's Syndrome at single-cell resolution.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: NOTCH pathway signaling significantly decreased in glandular, glandular secretory, and luminal subtypes, specifically in the JAG1-NOTCH2 ligand-receptor pair
    explanation: The source uses signaling language for a ligand-receptor expression inference.
  biological_processes:
  - preferred_term: Notch signaling pathway
    term:
      id: GO:0007219
      label: Notch signaling pathway
    modifier: DYSREGULATED
  downstream:
  - target: Reduced Receptive Endometrial Surface
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: A differentiation-related contribution is proposed; no intervention isolates NOTCH as the cause of human infertility.
    evidence:
    - reference: PMID:37735465
      reference_title: Decoding the endometrial niche of Asherman's Syndrome at single-cell resolution.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Our endometrial atlas highlights the loss of the endometrial epithelium, alterations to epithelial differentiation signaling pathways such as Wnt and Notch, and the appearance of characteristic epithelium expressing secretory leukocyte protease inhibitor during the window of implantation.
      explanation: Human recovered-cell and transcriptional observations; cell proportions are not stereological tissue-volume measurements.
      directness: INDIRECT
    hypothesis_groups:
    - niche_dysfunction
- name: Reduced Epithelial DIO2 Expression
  biological_scale: MOLECULAR
  description: Human IUA tissue shows lower DIO2 expression in selected assay subsets. Primary epithelial-cell knockdown and overexpression affect signaling and EMT-associated markers. Local tissue T3 showed a downward trend while serum thyroid measures were unchanged; this does not establish systemic hypothyroidism or measured DIO2 catalytic flux.
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/
    reference_title: Defective autophagy contributes to endometrial epithelial-mesenchymal transition in intrauterine adhesions - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: the mRNA and protein levels of DIO2 in endometria of IUA patients were significantly decreased to 40.97% and 30.80% of normal controls
    explanation: Human expression measurements in assay-specific tissue subsets; not a direct deiodinase activity assay.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/
    reference_title: Defective autophagy contributes to endometrial epithelial-mesenchymal transition in intrauterine adhesions - PMC
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Among them, si-1 was the most efficient siRNA which reduced the mRNA level to 39.75% and protein level to 61.86%
    explanation: Strongest screened DIO2 siRNA selected for downstream culture experiments.
  cell_types:
  - preferred_term: endometrial epithelial cell
    term:
      id: CL:0002149
      label: epithelial cell of uterus
  downstream:
  - target: Increased ERK Phosphorylation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: DIO2 knockdown is associated with increased ERK phosphorylation in culture; the intervening mechanism is unresolved.
    evidence:
    - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/
      reference_title: Defective autophagy contributes to endometrial epithelial-mesenchymal transition in intrauterine adhesions - PMC
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: significantly induced the phosphorylation of MAPK/ERK but not AMPK and AKT
      explanation: DIO2 knockdown-associated phosphorylation readout; intervening molecular events remain unresolved.
      directness: INDIRECT
    hypothesis_groups:
    - autophagy_defect_emt
- name: Increased ERK Phosphorylation
  biological_scale: MOLECULAR
  description: DIO2 knockdown increases MAPK/ERK phosphorylation in cultured endometrial epithelial cells; human tissue also shows an associated phosphorylation pattern. This is not evidence of direct DIO2-to-ERK binding.
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/
    reference_title: Defective autophagy contributes to endometrial epithelial-mesenchymal transition in intrauterine adhesions - PMC
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: significantly induced the phosphorylation of MAPK/ERK but not AMPK and AKT
    explanation: DIO2 knockdown-associated phosphorylation readout; intervening molecular events remain unresolved.
  downstream:
  - target: Increased MTOR Phosphorylation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: MEK-pathway inhibition reduces the MTOR-associated phosphorylation state after DIO2 knockdown, supporting indirect pathway involvement.
    evidence:
    - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/
      reference_title: Defective autophagy contributes to endometrial epithelial-mesenchymal transition in intrauterine adhesions - PMC
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: Meanwhile, we also observed that the activation of MTOR was inhibited by pre-treatment of U0126
      explanation: MEK-pathway inhibitor effect supports pathway involvement without demonstrating direct DIO2 binding or a direct kinase-substrate relationship.
      directness: INDIRECT
    hypothesis_groups:
    - autophagy_defect_emt
- name: Increased MTOR Phosphorylation
  biological_scale: MOLECULAR
  description: Phospho-MTOR is increased in the DIO2-perturbed culture context and reduced after U0126 pretreatment. The assay is an activation-associated readout and does not establish every kinase-substrate intermediate.
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/
    reference_title: Defective autophagy contributes to endometrial epithelial-mesenchymal transition in intrauterine adhesions - PMC
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Meanwhile, we also observed that the activation of MTOR was inhibited by pre-treatment of U0126
    explanation: MEK-pathway inhibitor effect supports pathway involvement without demonstrating direct DIO2 binding or a direct kinase-substrate relationship.
  downstream:
  - target: Reduced Epithelial Autophagy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: MTOR-associated signaling is proposed to suppress autophagy in this experimental context; no selective ATG genetic epistasis establishes the complete route.
    evidence:
    - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/
      reference_title: Defective autophagy contributes to endometrial epithelial-mesenchymal transition in intrauterine adhesions - PMC
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: Mechanistically, silencing DIO2 in EECs blocked autophagic flux and promoted EMT via the MAPK/ERK-MTOR pathway.
      explanation: Author mechanistic synthesis of culture perturbations, with static-marker and pharmacological limitations.
      directness: INDIRECT
    hypothesis_groups:
    - autophagy_defect_emt
- name: Reduced Epithelial Autophagy
  biological_scale: CELLULAR
  description: Human tissue and DIO2 culture experiments mainly show static autophagy-associated marker/structure changes. T3-associated chloroquine turnover provides dynamic flux support in culture; it should not be transferred to every human or DIO2 assay. Pharmacological effects support an autophagy-related hypothesis rather than a proven universal initiating lesion.
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/
    reference_title: Defective autophagy contributes to endometrial epithelial-mesenchymal transition in intrauterine adhesions - PMC
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: In endometrial epithelial cells (EECs), pharmacological inhibition of autophagy by chloroquine (CQ) promoted EEC-EMT, whereas enhanced autophagy by rapamycin extenuated this process.
    explanation: Pharmacological effects on epithelial/mesenchymal markers; not genetic epistasis or lineage tracing.
  cell_types:
  - preferred_term: endometrial epithelial cell
    term:
      id: CL:0002149
      label: epithelial cell of uterus
  biological_processes:
  - preferred_term: autophagy
    term:
      id: GO:0006914
      label: autophagy
    modifier: DECREASED
  downstream:
  - target: Epithelial Mesenchymal Marker Shift
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Chloroquine and rapamycin oppositely modify EMT-associated markers; drug pleiotropy and non-autophagic effects remain possible.
    evidence:
    - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/
      reference_title: Defective autophagy contributes to endometrial epithelial-mesenchymal transition in intrauterine adhesions - PMC
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: In endometrial epithelial cells (EECs), pharmacological inhibition of autophagy by chloroquine (CQ) promoted EEC-EMT, whereas enhanced autophagy by rapamycin extenuated this process.
      explanation: Pharmacological effects on epithelial/mesenchymal markers; not genetic epistasis or lineage tracing.
      directness: INDIRECT
    hypothesis_groups:
    - autophagy_defect_emt
- name: Epithelial Mesenchymal Marker Shift
  biological_scale: CELLULAR
  description: In experimental endometrial epithelial preparations, loss of epithelial markers and increases in mesenchymal markers indicate a partial EMT-like state. This does not show lineage-traced conversion into the complete human myofibroblast population or exclude resident stromal fibroblasts.
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/
    reference_title: Defective autophagy contributes to endometrial epithelial-mesenchymal transition in intrauterine adhesions - PMC
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Importantly, the cytoprotective effect of DIO2 overexpression was lost in the CQ pre-treated EECs
    explanation: Pharmacological blockade supports an autophagy-related contribution to the marker phenotype, with drug pleiotropy unresolved.
  - reference: PMID:37302615
    reference_title: Ferroptosis contributes to endometrial fibrosis in intrauterine adhesions.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: In vitro experiments showed that erastin-induced ferroptosis promoted EMT and fibrosis in endometrial epithelial cells (P < 0.05), but did not lead to pro-fibrotic differentiation in endometrial stromal cells (HESCs).
    explanation: Abstract-limited preparation-specific perturbation; epithelial and stromal responses differ.
  cell_types:
  - preferred_term: endometrial epithelial cell
    term:
      id: CL:0002149
      label: epithelial cell of uterus
  biological_processes:
  - preferred_term: epithelial to mesenchymal transition
    term:
      id: GO:0001837
      label: epithelial to mesenchymal transition
    modifier: INCREASED
- name: Epithelial Ferroptotic Stress
  biological_scale: CELLULAR
  description: A small human tissue comparison and pharmacological epithelial experiments implicate ferroptosis-related stress. The accessible abstract reports four severe IUA samples and four controls; detailed dosing, cell provenance and intervention specificity are not available from the full methods.
  evidence:
  - reference: PMID:37302615
    reference_title: Ferroptosis contributes to endometrial fibrosis in intrauterine adhesions.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: In the present study, we performed an RNA-seq of the endometria from 4 severe IUA patients and 4 normal controls.
    explanation: Small human discovery comparison.
  - reference: PMID:37302615
    reference_title: Ferroptosis contributes to endometrial fibrosis in intrauterine adhesions.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: In vitro experiments showed that erastin-induced ferroptosis promoted EMT and fibrosis in endometrial epithelial cells (P < 0.05), but did not lead to pro-fibrotic differentiation in endometrial stromal cells (HESCs).
    explanation: Abstract-limited preparation-specific perturbation; epithelial and stromal responses differ.
  cell_types:
  - preferred_term: endometrial epithelial cell
    term:
      id: CL:0002149
      label: epithelial cell of uterus
  downstream:
  - target: Epithelial Mesenchymal Marker Shift
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Erastin causes EMT-associated marker changes in epithelial preparations; this does not establish all injury-associated EMT as ferroptosis-dependent.
    evidence:
    - reference: PMID:37302615
      reference_title: Ferroptosis contributes to endometrial fibrosis in intrauterine adhesions.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: In vitro experiments showed that erastin-induced ferroptosis promoted EMT and fibrosis in endometrial epithelial cells (P < 0.05), but did not lead to pro-fibrotic differentiation in endometrial stromal cells (HESCs).
      explanation: Abstract-limited preparation-specific perturbation; epithelial and stromal responses differ.
      directness: INDIRECT
    hypothesis_groups:
    - ferroptosis_amplification
  - target: Epithelial Profibrotic Supernatant Activity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Supernatant from erastin-stimulated epithelial cells carries fibrogenic activity; the responsible mediator remains unidentified in the accessible source.
    evidence:
    - reference: PMID:37302615
      reference_title: Ferroptosis contributes to endometrial fibrosis in intrauterine adhesions.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: Cell co-culture experiments showed that erastin-stimulated epithelial cell supernatants promoted fibrosis in HESCs (P < 0.05).
      explanation: Transferable supernatant activity supports epithelial-stromal coupling; the responsible mediator is unresolved in the accessible abstract.
      directness: INDIRECT
    hypothesis_groups:
    - ferroptosis_amplification
- name: Epithelial Profibrotic Supernatant Activity
  biological_scale: CELLULAR
  description: Erastin-stimulated epithelial-cell supernatant promotes a fibrotic response in HESCs, whereas direct erastin exposure did not produce the same stromal differentiation response. This distinguishes a transferable epithelial influence from direct stromal ferroptosis.
  evidence:
  - reference: PMID:37302615
    reference_title: Ferroptosis contributes to endometrial fibrosis in intrauterine adhesions.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Cell co-culture experiments showed that erastin-stimulated epithelial cell supernatants promoted fibrosis in HESCs (P < 0.05).
    explanation: Transferable supernatant activity supports epithelial-stromal coupling; the responsible mediator is unresolved in the accessible abstract.
  downstream:
  - target: Stromal Fibrogenic Activation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The culture transfer experiment supports stromal response to epithelial supernatant without identifying the necessary secreted factor.
    evidence:
    - reference: PMID:37302615
      reference_title: Ferroptosis contributes to endometrial fibrosis in intrauterine adhesions.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: Cell co-culture experiments showed that erastin-stimulated epithelial cell supernatants promoted fibrosis in HESCs (P < 0.05).
      explanation: Transferable supernatant activity supports epithelial-stromal coupling; the responsible mediator is unresolved in the accessible abstract.
      directness: INDIRECT
    hypothesis_groups:
    - ferroptosis_amplification
- name: Stromal Fibrogenic Activation
  biological_scale: CELLULAR
  description: Endometrial stromal cells can develop a fibrogenic phenotype in experimental epithelial-stromal coupling. Resident stromal fibroblasts remain a plausible effector source; epithelial or endothelial marker coexpression does not establish their exclusive origin.
  evidence:
  - reference: PMID:37302615
    reference_title: Ferroptosis contributes to endometrial fibrosis in intrauterine adhesions.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Cell co-culture experiments showed that erastin-stimulated epithelial cell supernatants promoted fibrosis in HESCs (P < 0.05).
    explanation: Transferable supernatant activity supports epithelial-stromal coupling; the responsible mediator is unresolved in the accessible abstract.
  cell_types:
  - preferred_term: stromal cell of endometrium
    term:
      id: CL:0002255
      label: stromal cell of endometrium
  conforms_to: fibrotic_response#Mesenchymal Cell Activation
  downstream:
  - target: Excessive Endometrial Matrix Deposition
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Fibrogenic stromal activity can contribute to excess matrix; the relative human cellular sources and mediators remain unresolved.
    evidence:
    - reference: PMID:37302615
      reference_title: Ferroptosis contributes to endometrial fibrosis in intrauterine adhesions.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: Cell co-culture experiments showed that erastin-stimulated epithelial cell supernatants promoted fibrosis in HESCs (P < 0.05).
      explanation: Transferable supernatant activity supports epithelial-stromal coupling; the responsible mediator is unresolved in the accessible abstract.
      directness: INDIRECT
    - reference: PMID:39613882
      reference_title: Mechanistic insights into intrauterine adhesions.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: This damage leads to nonregenerative healing of endometrium resulting in replacement by fibrous connective tissue
      explanation: States the replacement of endometrium by fibrous connective tissue that this node asserts.
      directness: INDIRECT
- name: Endothelial Mesenchymal Marker Coexpression
  biological_scale: CELLULAR
  description: In a rat curettage-plus-LPS injury model, CD31/alpha-SMA double-positive cells and changing CD31, alpha-SMA and vimentin levels are consistent with an EndMT-like state. No endothelial lineage tracing, source fraction, selective perturbation or human conversion experiment establishes a fibroblast origin.
  evidence:
  - reference: PMID:34996477
    reference_title: 'EndMT: New findings on the origin of myofibroblasts in endometrial fibrosis of intrauterine adhesions.'
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: Immunofluorescence co-localization of CD31 and a-SMA showed that 14 days after moulding, double positive cells for CD31 and a-SMA could be clearly observed in the endometrium.
    explanation: CD31/alpha-SMA co-localization in the rat injury model; no endothelial lineage tracing quantifies conversion into fibroblasts.
  cell_types:
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  downstream:
  - target: Excessive Endometrial Matrix Deposition
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: An endothelial contribution is a model-derived hypothesis based on co-localized markers accompanying fibrosis, not proven lineage-mediated matrix production.
    evidence:
    - reference: PMID:34996477
      reference_title: 'EndMT: New findings on the origin of myofibroblasts in endometrial fibrosis of intrauterine adhesions.'
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: Immunofluorescence co-localization of CD31 and a-SMA showed that 14 days after moulding, double positive cells for CD31 and a-SMA could be clearly observed in the endometrium.
      explanation: CD31/alpha-SMA co-localization in the rat injury model; no endothelial lineage tracing quantifies conversion into fibroblasts.
      directness: INDIRECT
    hypothesis_groups:
    - endmt_source
- name: Excessive Endometrial Matrix Deposition
  biological_scale: TISSUE
  description: After some injuries, collagen-rich fibrous connective tissue replaces portions of regenerative endometrium. Scar extent and residual regenerative capacity vary; this does not require complete irreversible depletion of all epithelial progenitors.
  evidence:
  - reference: PMID:39613882
    reference_title: Mechanistic insights into intrauterine adhesions.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: This damage leads to nonregenerative healing of endometrium resulting in replacement by fibrous connective tissue
    explanation: States the replacement of endometrium by fibrous connective tissue that this node asserts.
  locations:
  - preferred_term: endometrium
    term:
      id: UBERON:0001295
      label: endometrium
  conforms_to: fibrotic_response#Excessive ECM Deposition
  downstream:
  - target: Intrauterine Adhesion Formation
    causal_link_type: DIRECT
    description: Fibrous tissue can bridge opposing endometrial surfaces and distort the cavity.
    evidence:
    - reference: PMID:39613882
      reference_title: Mechanistic insights into intrauterine adhesions.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: which bring about the adherence of opposing endometrium to render the uterine cavity and/or cervical canal partially or completely obliterated
      explanation: Describes exactly the bridging-of-opposing-surfaces geometry and the cavity/cervical obliteration this node asserts.
      directness: DIRECT
  - target: Reduced Receptive Endometrial Surface
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Replacement of functional endometrium can reduce suitable implantation surface, with additional functional and fertility factors remaining relevant.
    evidence:
    - reference: PMID:39613882
      reference_title: Mechanistic insights into intrauterine adhesions.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: This damage leads to nonregenerative healing of endometrium resulting in replacement by fibrous connective tissue
      explanation: States the replacement of endometrium by fibrous connective tissue that this node asserts.
      directness: INDIRECT
    - reference: PMID:30713131
      reference_title: 'Reproductive outcomes after surgical treatment of asherman syndrome: A systematic review.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: The pregnancy rate in women with severe adhesion was significantly lower than that in women with mild adhesion (P = 0.021).
      explanation: Selected post-adhesiolysis study synthesis supports a burden-outcome association, not an isolated assay of receptivity.
      directness: INDIRECT
  - target: Placenta accreta
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Prior endometrial scarring may disrupt the maternal placental interface; post-adhesiolysis cohort associations do not isolate this mechanism or prove that treatment itself is the sole cause.
    evidence:
    - reference: PMID:30713131
      reference_title: 'Reproductive outcomes after surgical treatment of asherman syndrome: A systematic review.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: 'placenta accreta syndrome was 10.1% (95% CI: 8.6 to 11.8) in 23 studies'
      explanation: A pooled post-adhesiolysis pregnancy complication, not an untreated disease frequency.
      directness: INDIRECT
- name: Intrauterine Adhesion Formation
  biological_scale: TISSUE
  description: Fibrous bands bridge uterine-cavity or endocervical surfaces. The lesion can partially or completely obstruct regions of the cavity; density, location and residual endometrium vary.
  evidence:
  - reference: PMID:39613882
    reference_title: Mechanistic insights into intrauterine adhesions.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: which bring about the adherence of opposing endometrium to render the uterine cavity and/or cervical canal partially or completely obliterated
    explanation: Describes exactly the bridging-of-opposing-surfaces geometry and the cavity/cervical obliteration this node asserts.
  locations:
  - preferred_term: uterus
    term:
      id: UBERON:0000995
      label: uterus
  conforms_to: fibrotic_response#Architectural Distortion and Organ Dysfunction
  downstream:
  - target: Intrauterine adhesions
    causal_link_type: DIRECT
    description: The pathological bands correspond to the observed defining lesion.
    evidence:
    - reference: PMID:39613882
      reference_title: Mechanistic insights into intrauterine adhesions.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: which bring about the adherence of opposing endometrium to render the uterine cavity and/or cervical canal partially or completely obliterated
      explanation: Describes exactly the bridging-of-opposing-surfaces geometry and the cavity/cervical obliteration this node asserts.
      directness: DIRECT
  - target: Menstrual Outflow Obstruction
    causal_link_type: DIRECT
    description: Adhesions involving the outflow tract may obstruct menstrual drainage; not every adhesion produces obstruction.
    evidence:
    - reference: PMID:21437822
      reference_title: Asherman's syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Most women with IUA have amenorrhea or hypomenorrhea, but up to a fourth have painless menses of normal flow and duration. Those who have amenorrhea may also have cyclic pelvic pain caused by outflow obstruction. The accompanying retrograde menstruation may lead to endometriosis.
      explanation: 'Single source for the whole node: the menstrual spectrum, the quarter-with-normal-menses caveat, the outflow-obstruction pain mechanism, and the retrograde-menstruation route to endometriosis.'
      directness: DIRECT
  - target: Female infertility
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Cavity distortion or ostial obstruction may impede reproduction, alongside endometrial and unrelated fertility factors.
    evidence:
    - reference: PMID:30713131
      reference_title: 'Reproductive outcomes after surgical treatment of asherman syndrome: A systematic review.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: The pregnancy rate in women with severe adhesion was significantly lower than that in women with mild adhesion (P = 0.021).
      explanation: Selected post-adhesiolysis study synthesis supports a burden-outcome association, not an isolated assay of receptivity.
      directness: INDIRECT
- name: Menstrual Outflow Obstruction
  biological_scale: TISSUE
  description: Adhesions can obstruct passage of menstrual effluent when functioning cycling endometrium remains. Reduced or absent external bleeding can coexist with retained blood and cyclic pain; normal menses does not exclude other clinically important adhesions.
  evidence:
  - reference: PMID:21437822
    reference_title: Asherman's syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Most women with IUA have amenorrhea or hypomenorrhea, but up to a fourth have painless menses of normal flow and duration. Those who have amenorrhea may also have cyclic pelvic pain caused by outflow obstruction. The accompanying retrograde menstruation may lead to endometriosis.
    explanation: 'Single source for the whole node: the menstrual spectrum, the quarter-with-normal-menses caveat, the outflow-obstruction pain mechanism, and the retrograde-menstruation route to endometriosis.'
  locations:
  - preferred_term: uterus
    term:
      id: UBERON:0000995
      label: uterus
  downstream:
  - target: Hypomenorrhea
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Partial obstruction may reduce external menstrual flow.
    evidence:
    - reference: PMID:21437822
      reference_title: Asherman's syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Most women with IUA have amenorrhea or hypomenorrhea, but up to a fourth have painless menses of normal flow and duration. Those who have amenorrhea may also have cyclic pelvic pain caused by outflow obstruction. The accompanying retrograde menstruation may lead to endometriosis.
      explanation: 'Single source for the whole node: the menstrual spectrum, the quarter-with-normal-menses caveat, the outflow-obstruction pain mechanism, and the retrograde-menstruation route to endometriosis.'
      directness: INDIRECT
  - target: Amenorrhea
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Complete outflow obstruction can prevent external bleeding.
    evidence:
    - reference: PMID:21437822
      reference_title: Asherman's syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Most women with IUA have amenorrhea or hypomenorrhea, but up to a fourth have painless menses of normal flow and duration. Those who have amenorrhea may also have cyclic pelvic pain caused by outflow obstruction. The accompanying retrograde menstruation may lead to endometriosis.
      explanation: 'Single source for the whole node: the menstrual spectrum, the quarter-with-normal-menses caveat, the outflow-obstruction pain mechanism, and the retrograde-menstruation route to endometriosis.'
      directness: INDIRECT
  - target: Cyclic pelvic pain
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Trapped cycling menstrual effluent can produce recurrent pain.
    evidence:
    - reference: PMID:21437822
      reference_title: Asherman's syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Most women with IUA have amenorrhea or hypomenorrhea, but up to a fourth have painless menses of normal flow and duration. Those who have amenorrhea may also have cyclic pelvic pain caused by outflow obstruction. The accompanying retrograde menstruation may lead to endometriosis.
      explanation: 'Single source for the whole node: the menstrual spectrum, the quarter-with-normal-menses caveat, the outflow-obstruction pain mechanism, and the retrograde-menstruation route to endometriosis.'
      directness: INDIRECT
  - target: Hematometra
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Outflow blockage may retain menstrual blood; it is not a universal manifestation.
    evidence:
    - reference: PMID:28603474
      reference_title: 'AAGL practice report: practice guidelines on intrauterine adhesions developed in collaboration with the European Society of Gynaecological Endoscopy (ESGE).'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: treatment should be considered only when there are signs or symptoms of pain, infertility, recurrent pregnancy loss, or menstrual abnormalities including hematometra.
      explanation: Guideline identifies retained menstrual blood among clinically relevant presentations.
      directness: INDIRECT
  - target: Secondary endometriosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Retrograde menstruation is a proposed possible contributor to coexisting endometriosis, without a demonstrated disease-wide risk.
    evidence:
    - reference: PMID:21437822
      reference_title: Asherman's syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Most women with IUA have amenorrhea or hypomenorrhea, but up to a fourth have painless menses of normal flow and duration. Those who have amenorrhea may also have cyclic pelvic pain caused by outflow obstruction. The accompanying retrograde menstruation may lead to endometriosis.
      explanation: 'Single source for the whole node: the menstrual spectrum, the quarter-with-normal-menses caveat, the outflow-obstruction pain mechanism, and the retrograde-menstruation route to endometriosis.'
      directness: INDIRECT
- name: Reduced Receptive Endometrial Surface
  biological_scale: TISSUE
  description: Scarring, reduced epithelial coverage and altered differentiation may reduce functional implantation surface. Hysteroscopic patency, transcriptional signatures and actual reproductive competence are distinct measurements; associated fertility impairment is not solely attributable to one pathway.
  evidence:
  - reference: PMID:37735465
    reference_title: Decoding the endometrial niche of Asherman's Syndrome at single-cell resolution.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Our endometrial atlas highlights the loss of the endometrial epithelium, alterations to epithelial differentiation signaling pathways such as Wnt and Notch, and the appearance of characteristic epithelium expressing secretory leukocyte protease inhibitor during the window of implantation.
    explanation: Human recovered-cell and transcriptional observations; cell proportions are not stereological tissue-volume measurements.
  - reference: PMID:30713131
    reference_title: 'Reproductive outcomes after surgical treatment of asherman syndrome: A systematic review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: The pregnancy rate in women with severe adhesion was significantly lower than that in women with mild adhesion (P = 0.021).
    explanation: Selected post-adhesiolysis study synthesis supports a burden-outcome association, not an isolated assay of receptivity.
  locations:
  - preferred_term: endometrium
    term:
      id: UBERON:0001295
      label: endometrium
  downstream:
  - target: Female infertility
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: A deficient implantation environment may contribute to infertility; this is a clinical inference rather than pathway-specific causal proof.
    evidence:
    - reference: PMID:30713131
      reference_title: 'Reproductive outcomes after surgical treatment of asherman syndrome: A systematic review.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: The pregnancy rate in women with severe adhesion was significantly lower than that in women with mild adhesion (P = 0.021).
      explanation: Selected post-adhesiolysis study synthesis supports a burden-outcome association, not an isolated assay of receptivity.
      directness: INDIRECT
  - target: Recurrent pregnancy loss
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Abnormal residual endometrium may contribute to pregnancy loss after implantation; infertility and miscarriage are distinct endpoints with multiple possible causes.
    evidence:
    - reference: PMID:37735465
      reference_title: Decoding the endometrial niche of Asherman's Syndrome at single-cell resolution.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: Asherman's Syndrome is characterized by intrauterine adhesions or scarring, which cause infertility, menstrual abnormalities, and recurrent pregnancy loss.
      explanation: Clinical background identifies reproductive dysfunction; the specific intermediate mechanism is not measured.
      directness: INDIRECT
animal_models:
- name: Rat mechanical-plus-LPS uterine injury
  species: Rat
  background: Eight-week-old female Sprague-Dawley rats
  publication: PMID:34996477
  description: Uterine scraping plus an intrauterine LPS-bearing thread retained for 48 hours produces fibrosis, reduced glands and adhesion-associated histology. Observations at days 3, 7, 14 and 28 include CD31/alpha-SMA co-localization at day 14.
  notes: The injury can extend into myometrium and models severe acute injury. No endothelial lineage tracing, selective conversion blockade, source fraction or human validation is provided. Marker coexpression cannot establish all fibroblasts as endothelial-derived; sample-size reporting is limited.
  modeled_mechanisms:
  - target: Endothelial Mesenchymal Marker Coexpression
    relationship: MEASURES
    description: CD31 and alpha-SMA double-positive cells are observed after injury.
    evidence:
    - reference: PMID:34996477
      reference_title: 'EndMT: New findings on the origin of myofibroblasts in endometrial fibrosis of intrauterine adhesions.'
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: Immunofluorescence co-localization of CD31 and a-SMA showed that 14 days after moulding, double positive cells for CD31 and a-SMA could be clearly observed in the endometrium.
      explanation: CD31/alpha-SMA co-localization in the rat injury model; no endothelial lineage tracing quantifies conversion into fibroblasts.
    readouts:
    - name: CD31/alpha-SMA co-localization
      target: Endothelial Mesenchymal Marker Coexpression
      direction: INCREASED
      interpretation: CD31 and alpha-SMA double-positive cells are observed after injury.
      evidence:
      - reference: PMID:34996477
        reference_title: 'EndMT: New findings on the origin of myofibroblasts in endometrial fibrosis of intrauterine adhesions.'
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        quote_role: PRIMARY_RESULT
        snippet: Immunofluorescence co-localization of CD31 and a-SMA showed that 14 days after moulding, double positive cells for CD31 and a-SMA could be clearly observed in the endometrium.
        explanation: CD31/alpha-SMA co-localization in the rat injury model; no endothelial lineage tracing quantifies conversion into fibroblasts.
  - target: Excessive Endometrial Matrix Deposition
    relationship: PARTIALLY_RECAPITULATES
    description: The injury model produces histological fibrosis, with model-specific inflammatory injury.
    evidence:
    - reference: PMID:34996477
      reference_title: 'EndMT: New findings on the origin of myofibroblasts in endometrial fibrosis of intrauterine adhesions.'
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: After 7 days, adhesive bands were visible in the uterine cavity, which was reduced or even completely closed, and the area of fibrosis was significantly increased compared with that in the control group.
      explanation: Actual time-specific histological result in the dual-injury rat model.
    limitations: Acute dual injury does not reproduce every human procedure or chronic niche.
    readouts:
    - name: Histological fibrotic area at day 7
      target: Excessive Endometrial Matrix Deposition
      direction: INCREASED
      interpretation: Masson-stained fibrosis area is increased versus the model control.
      evidence:
      - reference: PMID:34996477
        reference_title: 'EndMT: New findings on the origin of myofibroblasts in endometrial fibrosis of intrauterine adhesions.'
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        quote_role: PRIMARY_RESULT
        snippet: After 7 days, adhesive bands were visible in the uterine cavity, which was reduced or even completely closed, and the area of fibrosis was significantly increased compared with that in the control group.
        explanation: Actual time-specific histological result in the dual-injury rat model.
  evidence:
  - reference: PMID:34996477
    reference_title: 'EndMT: New findings on the origin of myofibroblasts in endometrial fibrosis of intrauterine adhesions.'
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: To create an infection injury, bacterial lipopolysaccharide (LPS) surgical cotton thread was left in the uterine cavity
    explanation: Dual mechanical and inflammatory injury, not a mechanical-only rat model.
  - reference: PMID:34996477
    reference_title: 'EndMT: New findings on the origin of myofibroblasts in endometrial fibrosis of intrauterine adhesions.'
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: Immunofluorescence co-localization of CD31 and a-SMA showed that 14 days after moulding, double positive cells for CD31 and a-SMA could be clearly observed in the endometrium.
    explanation: CD31/alpha-SMA co-localization in the rat injury model; no endothelial lineage tracing quantifies conversion into fibroblasts.
- name: Mouse uterine injury with autophagy-pathway drugs
  species: Mouse
  background: Adult eight-week-old female C57BL/6 mice
  publication: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/
  description: Curettage plus intrauterine LPS produces an IUA-like injury. Chloroquine and rapamycin begin two hours before surgery and continue for two weeks; T3 is administered on days 6–15. Histological fibrosis and epithelial/mesenchymal markers are measured, with four mice per group.
  notes: Rapamycin is preventive attenuation in this protocol rather than delayed clinical rescue. Chloroquine alone gives a mild nonsignificant fibrosis/EMT trend; injury initiates the model. No pregnancy or live-birth endpoint is measured. The paper inconsistently reports T3 as 40 mg/kg in Methods/Figure 8 and 40 micrograms/kg/day in Discussion; no dose is promoted as a clinical regimen. A mouse DIO2 gene-therapy experiment is not reported.
  modeled_mechanisms:
  - target: Reduced Epithelial Autophagy
    relationship: PERTURBS
    description: Autophagy-related drugs alter marker readouts in injured uterus.
    evidence:
    - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/
      reference_title: Defective autophagy contributes to endometrial epithelial-mesenchymal transition in intrauterine adhesions - PMC
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: in an IUA-like mouse model, the autophagy in endometrium was defective accompanied by EEC-EMT, and CQ could inhibit autophagy and aggravate endometrial fibrosis, whereas rapamycin or T3 treatment could improve the autophagic levels and blunt endometrial fibrosis
      explanation: Mouse histology and marker findings; prophylactic rapamycin and later T3 differ in timing.
    limitations: Pharmacological specificity and human flux mediation are unresolved.
  - target: Excessive Endometrial Matrix Deposition
    relationship: PARTIALLY_RECAPITULATES
    description: Histological fibrosis is attenuated under the reported rapamycin and T3 schedules.
    evidence:
    - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/
      reference_title: Defective autophagy contributes to endometrial epithelial-mesenchymal transition in intrauterine adhesions - PMC
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: in an IUA-like mouse model, the autophagy in endometrium was defective accompanied by EEC-EMT, and CQ could inhibit autophagy and aggravate endometrial fibrosis, whereas rapamycin or T3 treatment could improve the autophagic levels and blunt endometrial fibrosis
      explanation: Mouse histology and marker findings; prophylactic rapamycin and later T3 differ in timing.
    readouts:
    - name: Histological fibrosis after rapamycin or T3
      target: Excessive Endometrial Matrix Deposition
      direction: DECREASED
      interpretation: Histological fibrosis is attenuated under the reported rapamycin and T3 schedules.
      evidence:
      - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/
        reference_title: Defective autophagy contributes to endometrial epithelial-mesenchymal transition in intrauterine adhesions - PMC
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        quote_role: PRIMARY_RESULT
        snippet: in an IUA-like mouse model, the autophagy in endometrium was defective accompanied by EEC-EMT, and CQ could inhibit autophagy and aggravate endometrial fibrosis, whereas rapamycin or T3 treatment could improve the autophagic levels and blunt endometrial fibrosis
        explanation: Mouse histology and marker findings; prophylactic rapamycin and later T3 differ in timing.
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/
    reference_title: Defective autophagy contributes to endometrial epithelial-mesenchymal transition in intrauterine adhesions - PMC
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: in an IUA-like mouse model, the autophagy in endometrium was defective accompanied by EEC-EMT, and CQ could inhibit autophagy and aggravate endometrial fibrosis, whereas rapamycin or T3 treatment could improve the autophagic levels and blunt endometrial fibrosis
    explanation: Mouse histology and marker findings; prophylactic rapamycin and later T3 differ in timing.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/
    reference_title: Defective autophagy contributes to endometrial epithelial-mesenchymal transition in intrauterine adhesions - PMC
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: For the pharmacological alteration of autophagy treatment, the mice received CQ (60 mg/kg/d) or rapamycin (2 mg/kg/d) intraperitoneal injection at 2 h prior to surgery and continuously received CQ or rapamycin for 2 weeks.
    explanation: The dosing schedule establishes prophylactic timing.
- name: Mouse ferroptosis perturbation in uterine injury
  species: Mouse
  publication: PMID:37302615
  description: The accessible abstract reports mild endometrial EMT/fibrosis after erastin and reduced fibrosis with ferrostatin-1 in a dual-injury IUA model.
  notes: Full experimental methods were unavailable after canonical and primary-publisher retrieval attempts. Strain, dose, intervention timing and group sizes are not inferred. Pharmacological effects do not establish clinical efficacy or exclusive ferroptosis mediation.
  modeled_mechanisms:
  - target: Epithelial Ferroptotic Stress
    relationship: PERTURBS
    description: Erastin and ferrostatin-1 perturb a ferroptosis-associated injury model.
    evidence:
    - reference: PMID:37302615
      reference_title: Ferroptosis contributes to endometrial fibrosis in intrauterine adhesions.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: Meanwhile, the ferroptosis inhibitor Fer-1 significantly ameliorated endometrial fibrosis in a dual-injury IUA murine model.
      explanation: Abstract-limited pharmacological model result, not established human treatment.
  - target: Excessive Endometrial Matrix Deposition
    relationship: PARTIALLY_RECAPITULATES
    description: Ferrostatin-1 is associated with reduced experimental endometrial fibrosis.
    evidence:
    - reference: PMID:37302615
      reference_title: Ferroptosis contributes to endometrial fibrosis in intrauterine adhesions.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: Meanwhile, the ferroptosis inhibitor Fer-1 significantly ameliorated endometrial fibrosis in a dual-injury IUA murine model.
      explanation: Abstract-limited pharmacological model result, not established human treatment.
    readouts:
    - name: Endometrial fibrosis after ferrostatin-1
      target: Excessive Endometrial Matrix Deposition
      direction: DECREASED
      interpretation: Ferrostatin-1 is associated with reduced experimental endometrial fibrosis.
      evidence:
      - reference: PMID:37302615
        reference_title: Ferroptosis contributes to endometrial fibrosis in intrauterine adhesions.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        quote_role: PRIMARY_RESULT
        snippet: Meanwhile, the ferroptosis inhibitor Fer-1 significantly ameliorated endometrial fibrosis in a dual-injury IUA murine model.
        explanation: Abstract-limited pharmacological model result, not established human treatment.
  evidence:
  - reference: PMID:37302615
    reference_title: Ferroptosis contributes to endometrial fibrosis in intrauterine adhesions.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: Meanwhile, the ferroptosis inhibitor Fer-1 significantly ameliorated endometrial fibrosis in a dual-injury IUA murine model.
    explanation: Abstract-limited pharmacological model result, not established human treatment.
experimental_models:
- name: Primary endometrial epithelial DIO2 perturbation
  experimental_model_type: PRIMARY_CELL_CULTURE
  organism:
    preferred_term: Homo sapiens
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: Primary human endometrial epithelial cultures; individual donor independence is not established for every assay
  cell_types:
  - preferred_term: endometrial epithelial cell
    term:
      id: CL:0002149
      label: epithelial cell of uterus
  publication: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/
  description: The strongest of three screened DIO2 siRNAs and a DIO2 overexpression construct alter ERK/MTOR phosphorylation, autophagy-associated markers and epithelial/mesenchymal markers. Chloroquine blockade and U0126 pretreatment test pharmacological pathway dependence.
  notes: No siRNA-resistant rescue, catalytic-dead comparison, direct DIO2-to-ERK binding assay or genetic ATG epistasis is reported. Most DIO2 assays are static marker/structure measurements. The paper uses Ishikawa cells for CCK-8 viability, so that reassurance is not assigned to all primary EEC exposures. Marker shifts do not trace a human fibroblast lineage.
  modeled_mechanisms:
  - target: Reduced Epithelial DIO2 Expression
    relationship: PERTURBS
    description: DIO2 si-1 reduces DIO2 RNA and protein.
    evidence:
    - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/
      reference_title: Defective autophagy contributes to endometrial epithelial-mesenchymal transition in intrauterine adhesions - PMC
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: Among them, si-1 was the most efficient siRNA which reduced the mRNA level to 39.75% and protein level to 61.86%
      explanation: Strongest screened DIO2 siRNA selected for downstream culture experiments.
    readouts:
    - name: DIO2 expression after si-1
      target: Reduced Epithelial DIO2 Expression
      direction: DECREASED
      interpretation: DIO2 si-1 reduces DIO2 RNA and protein.
      evidence:
      - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/
        reference_title: Defective autophagy contributes to endometrial epithelial-mesenchymal transition in intrauterine adhesions - PMC
        supports: SUPPORT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        snippet: Among them, si-1 was the most efficient siRNA which reduced the mRNA level to 39.75% and protein level to 61.86%
        explanation: Strongest screened DIO2 siRNA selected for downstream culture experiments.
  - target: Increased ERK Phosphorylation
    relationship: MEASURES
    description: DIO2 knockdown increases MAPK/ERK phosphorylation.
    evidence:
    - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/
      reference_title: Defective autophagy contributes to endometrial epithelial-mesenchymal transition in intrauterine adhesions - PMC
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: significantly induced the phosphorylation of MAPK/ERK but not AMPK and AKT
      explanation: DIO2 knockdown-associated phosphorylation readout; intervening molecular events remain unresolved.
    readouts:
    - name: ERK phosphorylation
      target: Increased ERK Phosphorylation
      direction: INCREASED
      interpretation: DIO2 knockdown increases MAPK/ERK phosphorylation.
      evidence:
      - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/
        reference_title: Defective autophagy contributes to endometrial epithelial-mesenchymal transition in intrauterine adhesions - PMC
        supports: SUPPORT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        snippet: significantly induced the phosphorylation of MAPK/ERK but not AMPK and AKT
        explanation: DIO2 knockdown-associated phosphorylation readout; intervening molecular events remain unresolved.
  - target: Epithelial Mesenchymal Marker Shift
    relationship: MEASURES
    description: Chloroquine removes the marker benefit associated with DIO2 overexpression.
    evidence:
    - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/
      reference_title: Defective autophagy contributes to endometrial epithelial-mesenchymal transition in intrauterine adhesions - PMC
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: Importantly, the cytoprotective effect of DIO2 overexpression was lost in the CQ pre-treated EECs
      explanation: Pharmacological blockade supports an autophagy-related contribution to the marker phenotype, with drug pleiotropy unresolved.
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/
    reference_title: Defective autophagy contributes to endometrial epithelial-mesenchymal transition in intrauterine adhesions - PMC
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Among them, si-1 was the most efficient siRNA which reduced the mRNA level to 39.75% and protein level to 61.86%
    explanation: Strongest screened DIO2 siRNA selected for downstream culture experiments.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/
    reference_title: Defective autophagy contributes to endometrial epithelial-mesenchymal transition in intrauterine adhesions - PMC
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: significantly induced the phosphorylation of MAPK/ERK but not AMPK and AKT
    explanation: DIO2 knockdown-associated phosphorylation readout; intervening molecular events remain unresolved.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/
    reference_title: Defective autophagy contributes to endometrial epithelial-mesenchymal transition in intrauterine adhesions - PMC
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Importantly, the cytoprotective effect of DIO2 overexpression was lost in the CQ pre-treated EECs
    explanation: Pharmacological blockade supports an autophagy-related contribution to the marker phenotype, with drug pleiotropy unresolved.
- name: Primary epithelial pharmacological autophagy assay
  experimental_model_type: PRIMARY_CELL_CULTURE
  organism:
    preferred_term: Homo sapiens
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: Primary human endometrial epithelial cells
  publication: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/
  description: Chloroquine, rapamycin and T3 perturb autophagy-associated and epithelial/mesenchymal readouts. The T3 plus chloroquine comparison is the explicit dynamic turnover experiment.
  notes: Drug effects support pharmacological mediation with unresolved pleiotropy. No human fertility endpoint or transplant outcome is measured.
  modeled_mechanisms:
  - target: Reduced Epithelial Autophagy
    relationship: PERTURBS
    description: T3 increases autophagic turnover in the lysosomal-blockade comparison.
    evidence:
    - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/
      reference_title: Defective autophagy contributes to endometrial epithelial-mesenchymal transition in intrauterine adhesions - PMC
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: CQ and T3 treatment significantly increased LC3B-II levels compared to T3 or CQ alone suggesting that T3 increased autophagic flux in EECs.
      explanation: Lysosomal-blockade turnover supports dynamic T3-associated flux in culture; other marker assays are not equivalent.
    readouts:
    - name: T3-associated autophagic flux
      target: Reduced Epithelial Autophagy
      direction: INCREASED
      interpretation: T3 increases autophagic turnover in the lysosomal-blockade comparison.
      evidence:
      - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/
        reference_title: Defective autophagy contributes to endometrial epithelial-mesenchymal transition in intrauterine adhesions - PMC
        supports: SUPPORT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        snippet: CQ and T3 treatment significantly increased LC3B-II levels compared to T3 or CQ alone suggesting that T3 increased autophagic flux in EECs.
        explanation: Lysosomal-blockade turnover supports dynamic T3-associated flux in culture; other marker assays are not equivalent.
  - target: Epithelial Mesenchymal Marker Shift
    relationship: MEASURES
    description: Chloroquine and rapamycin have opposing EMT-marker effects.
    evidence:
    - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/
      reference_title: Defective autophagy contributes to endometrial epithelial-mesenchymal transition in intrauterine adhesions - PMC
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: In endometrial epithelial cells (EECs), pharmacological inhibition of autophagy by chloroquine (CQ) promoted EEC-EMT, whereas enhanced autophagy by rapamycin extenuated this process.
      explanation: Pharmacological effects on epithelial/mesenchymal markers; not genetic epistasis or lineage tracing.
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/
    reference_title: Defective autophagy contributes to endometrial epithelial-mesenchymal transition in intrauterine adhesions - PMC
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: In endometrial epithelial cells (EECs), pharmacological inhibition of autophagy by chloroquine (CQ) promoted EEC-EMT, whereas enhanced autophagy by rapamycin extenuated this process.
    explanation: Pharmacological effects on epithelial/mesenchymal markers; not genetic epistasis or lineage tracing.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/
    reference_title: Defective autophagy contributes to endometrial epithelial-mesenchymal transition in intrauterine adhesions - PMC
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: CQ and T3 treatment significantly increased LC3B-II levels compared to T3 or CQ alone suggesting that T3 increased autophagic flux in EECs.
    explanation: Lysosomal-blockade turnover supports dynamic T3-associated flux in culture; other marker assays are not equivalent.
- name: Epithelial-supernatant stromal fibrosis assay
  experimental_model_type: CO_CULTURE
  cell_source: Endometrial epithelial and human endometrial stromal preparations reported in the abstract; further provenance unavailable
  publication: PMID:37302615
  description: Erastin-induced epithelial stress promotes EMT/fibrosis markers, whereas direct erastin does not induce stromal fibrogenic differentiation. Transfer of stimulated epithelial supernatant promotes the stromal response.
  notes: The abstract calls this a co-culture experiment; the accessible record does not establish simultaneous contact culture, the necessary soluble mediator, dose or donor replication. No mediator-neutralization result or direct epithelial lineage conversion is inferred.
  modeled_mechanisms:
  - target: Epithelial Profibrotic Supernatant Activity
    relationship: MEASURES
    description: Supernatant carries transferable fibrogenic activity.
    evidence:
    - reference: PMID:37302615
      reference_title: Ferroptosis contributes to endometrial fibrosis in intrauterine adhesions.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: Cell co-culture experiments showed that erastin-stimulated epithelial cell supernatants promoted fibrosis in HESCs (P < 0.05).
      explanation: Transferable supernatant activity supports epithelial-stromal coupling; the responsible mediator is unresolved in the accessible abstract.
  - target: Stromal Fibrogenic Activation
    relationship: PERTURBS
    description: HESC fibrotic response increases after stimulated epithelial supernatant.
    evidence:
    - reference: PMID:37302615
      reference_title: Ferroptosis contributes to endometrial fibrosis in intrauterine adhesions.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: Cell co-culture experiments showed that erastin-stimulated epithelial cell supernatants promoted fibrosis in HESCs (P < 0.05).
      explanation: Transferable supernatant activity supports epithelial-stromal coupling; the responsible mediator is unresolved in the accessible abstract.
    readouts:
    - name: Stromal fibrotic response
      target: Stromal Fibrogenic Activation
      direction: INCREASED
      interpretation: HESC fibrotic response increases after stimulated epithelial supernatant.
      evidence:
      - reference: PMID:37302615
        reference_title: Ferroptosis contributes to endometrial fibrosis in intrauterine adhesions.
        supports: SUPPORT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        snippet: Cell co-culture experiments showed that erastin-stimulated epithelial cell supernatants promoted fibrosis in HESCs (P < 0.05).
        explanation: Transferable supernatant activity supports epithelial-stromal coupling; the responsible mediator is unresolved in the accessible abstract.
  evidence:
  - reference: PMID:37302615
    reference_title: Ferroptosis contributes to endometrial fibrosis in intrauterine adhesions.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: In vitro experiments showed that erastin-induced ferroptosis promoted EMT and fibrosis in endometrial epithelial cells (P < 0.05), but did not lead to pro-fibrotic differentiation in endometrial stromal cells (HESCs).
    explanation: Abstract-limited preparation-specific perturbation; epithelial and stromal responses differ.
  - reference: PMID:37302615
    reference_title: Ferroptosis contributes to endometrial fibrosis in intrauterine adhesions.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Cell co-culture experiments showed that erastin-stimulated epithelial cell supernatants promoted fibrosis in HESCs (P < 0.05).
    explanation: Transferable supernatant activity supports epithelial-stromal coupling; the responsible mediator is unresolved in the accessible abstract.
- name: Patient-derived endometrial epithelial organoids
  experimental_model_type: ORGANOID
  organism:
    preferred_term: Homo sapiens
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: Three Asherman and three healthy-control endometrial donors; Asherman donors overlap the tissue cohort
  publication: PMID:37735465
  description: Hormone-treated passage-two organoids were profiled by single-cell RNA sequencing. Transcriptomic identities were assigned with a reference-trained classifier and compared between groups. AS organoid transcriptomic profiles differed from controls, particularly in glandular secretory epithelium; that result is not equated with the tissue-derived reduced-WNT communication signature.
  notes: Passage-two culture enriches organoid-forming cells. WNT inhibitor XAV939 in culture may mask differences; hormonal and selection effects limit extrapolation to untreated tissue. These assays neither trace progenitor fate nor show pathway-specific rescue or clinical cell-therapy efficacy.
  evidence:
  - reference: PMID:37735465
    reference_title: Decoding the endometrial niche of Asherman's Syndrome at single-cell resolution.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Organoids were generated from AS patients’ endometrium (n = 3) and from healthy control (n = 3) endometrium
    explanation: Three AS organoid donors overlap the nine-person human atlas cohort.
  - reference: PMID:37735465
    reference_title: Decoding the endometrial niche of Asherman's Syndrome at single-cell resolution.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Additionally, we obtained single-cell EEO results at P2, with a technical enrichment of organoid-forming cells, while the presence of XAV939 (a WNT inhibitor) in the EEO culture media may mask significant differences.
    explanation: Authors explicitly limit interpretation of the organoid comparison.
  - reference: PMID:37735465
    reference_title: Decoding the endometrial niche of Asherman's Syndrome at single-cell resolution.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: the transcriptomic profile of AS EEO cells became significantly different from WOI control EEO cells and in vivo counterparts, especially in the glandular secretory epithelium
    explanation: Actual organoid transcriptional comparison; this does not establish an isolated WNT readout.
biochemical:
- name: SLPI-positive endometrial epithelial state
  presence: INCREASED
  context: Research biopsy single-cell RNA and RNAscope in the secretory/window-of-implantation setting
  notes: An SLPI-expressing stress-associated epithelial state was observed in selected AS tissue. RNAscope localizes RNA; it does not establish secreted protein concentration, diagnostic sensitivity/specificity or an established clinical biomarker. Hormonal synchronization and biopsy selection limit generalization.
  evidence:
  - reference: PMID:37735465
    reference_title: Decoding the endometrial niche of Asherman's Syndrome at single-cell resolution.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: RNAscope experiments localized SLPI+ cells to the luminal and glandular epithelium of AS patients
    explanation: Localization of a research transcriptomic state, not a validated diagnostic test.
mechanistic_hypotheses:
- hypothesis_group_id: niche_dysfunction
  hypothesis_label: Altered epithelial differentiation within a dysfunctional niche
  status: EMERGING
  description: Human transcriptional and inferred communication differences suggest altered epithelial differentiation. Cross-sectional composition, HRT exposure and control-dataset differences do not establish WNT or NOTCH as necessary causal routes.
  evidence:
  - reference: PMID:37735465
    reference_title: Decoding the endometrial niche of Asherman's Syndrome at single-cell resolution.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Our endometrial atlas highlights the loss of the endometrial epithelium, alterations to epithelial differentiation signaling pathways such as Wnt and Notch, and the appearance of characteristic epithelium expressing secretory leukocyte protease inhibitor during the window of implantation.
    explanation: Human recovered-cell and transcriptional observations; cell proportions are not stereological tissue-volume measurements.
- hypothesis_group_id: autophagy_defect_emt
  hypothesis_label: DIO2-associated autophagy changes amplify epithelial stress
  status: EMERGING
  description: DIO2 perturbation, phosphorylation readouts and pharmacological interventions support an experimental autophagy-related contribution to partial EMT-like changes. Static human markers are not direct dynamic flux assays, and no complete genetic mediation chain or human treatment benefit is established.
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/
    reference_title: Defective autophagy contributes to endometrial epithelial-mesenchymal transition in intrauterine adhesions - PMC
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: In endometrial epithelial cells (EECs), pharmacological inhibition of autophagy by chloroquine (CQ) promoted EEC-EMT, whereas enhanced autophagy by rapamycin extenuated this process.
    explanation: Pharmacological effects on epithelial/mesenchymal markers; not genetic epistasis or lineage tracing.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/
    reference_title: Defective autophagy contributes to endometrial epithelial-mesenchymal transition in intrauterine adhesions - PMC
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Importantly, the cytoprotective effect of DIO2 overexpression was lost in the CQ pre-treated EECs
    explanation: Pharmacological blockade supports an autophagy-related contribution to the marker phenotype, with drug pleiotropy unresolved.
- hypothesis_group_id: ferroptosis_amplification
  hypothesis_label: Ferroptotic epithelial stress promotes stromal fibrosis through transferable signals
  status: EMERGING
  description: Erastin affects epithelial preparations and their supernatant promotes stromal fibrosis, unlike direct stromal exposure. The necessary secreted mediator, pathway specificity and human causal sequence remain unresolved.
  evidence:
  - reference: PMID:37302615
    reference_title: Ferroptosis contributes to endometrial fibrosis in intrauterine adhesions.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: In vitro experiments showed that erastin-induced ferroptosis promoted EMT and fibrosis in endometrial epithelial cells (P < 0.05), but did not lead to pro-fibrotic differentiation in endometrial stromal cells (HESCs).
    explanation: Abstract-limited preparation-specific perturbation; epithelial and stromal responses differ.
  - reference: PMID:37302615
    reference_title: Ferroptosis contributes to endometrial fibrosis in intrauterine adhesions.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Cell co-culture experiments showed that erastin-stimulated epithelial cell supernatants promoted fibrosis in HESCs (P < 0.05).
    explanation: Transferable supernatant activity supports epithelial-stromal coupling; the responsible mediator is unresolved in the accessible abstract.
- hypothesis_group_id: endmt_source
  hypothesis_label: Endothelial marker transitions may contribute to fibrosis
  status: EMERGING
  description: Rat CD31/alpha-SMA co-localization motivates an endothelial-source hypothesis. It does not quantify lineage conversion or establish that human myofibroblasts arise from endothelium.
  evidence:
  - reference: PMID:34996477
    reference_title: 'EndMT: New findings on the origin of myofibroblasts in endometrial fibrosis of intrauterine adhesions.'
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: Immunofluorescence co-localization of CD31 and a-SMA showed that 14 days after moulding, double positive cells for CD31 and a-SMA could be clearly observed in the endometrium.
    explanation: CD31/alpha-SMA co-localization in the rat injury model; no endothelial lineage tracing quantifies conversion into fibroblasts.
discussions:
- discussion_id: gap_regenerative_capacity
  kind: KNOWLEDGE_GAP
  prompt: Which injury and niche features determine regeneration versus persistent scarring?
  rationale: Residual epithelial populations, injury depth, hormonal state, inflammatory context and niche interactions may all matter. Existing evidence does not identify one necessary switch or prove that complete progenitor depletion is required. The contribution of epithelial/stromal plasticity is species- and injury-dependent.
  attaches_to:
  - pathophysiology#Endometrial Basal Layer Injury
  - pathophysiology#Excessive Endometrial Matrix Deposition
  evidence:
  - reference: PMID:37843929
    reference_title: Mechanisms of Regeneration and Fibrosis in the Endometrium.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: In the endometrium, the diversion of healing towards a fibrotic outcome is often attributed to the obliteration of the stem cell reservoir during injury. However, this model is complicated by the observation that diverse cell populations may contribute to re-epithelialization of the endometrium
    explanation: Review explicitly challenges a simple complete-progenitor-loss account.
  proposed_experiments:
  - experiment_id: exp_matched_injury_niche
    name: Matched longitudinal injury and repair profiling
    description: Compare defined injury depths and hormonal states with serial tissue histology, epithelial coverage and validated lineage tracing in an appropriate model. Match human observational samples by cycle, treatment and sampling location rather than infer temporality from one biopsy.
- discussion_id: gap_cellular_origins
  kind: KNOWLEDGE_GAP
  prompt: Which cells contribute to the fibrogenic effector pool in human adhesion disease?
  rationale: Partial EMT markers, CD31/alpha-SMA co-localization and transcriptomic intermediate states do not by themselves trace cellular origin. The rat experiment uses scraping plus LPS and has no endothelial lineage tracing. Lack of an EndMT conclusion in the human atlas is not a negative test of the hypothesis; resident stromal fibroblasts cannot be excluded.
  attaches_to:
  - pathophysiology#Epithelial Mesenchymal Marker Shift
  - pathophysiology#Endothelial Mesenchymal Marker Coexpression
  - pathophysiology#Stromal Fibrogenic Activation
  evidence:
  - reference: PMID:34996477
    reference_title: 'EndMT: New findings on the origin of myofibroblasts in endometrial fibrosis of intrauterine adhesions.'
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: Immunofluorescence co-localization of CD31 and a-SMA showed that 14 days after moulding, double positive cells for CD31 and a-SMA could be clearly observed in the endometrium.
    explanation: CD31/alpha-SMA co-localization in the rat injury model; no endothelial lineage tracing quantifies conversion into fibroblasts.
  - reference: PMID:37302615
    reference_title: Ferroptosis contributes to endometrial fibrosis in intrauterine adhesions.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Cell co-culture experiments showed that erastin-stimulated epithelial cell supernatants promoted fibrosis in HESCs (P < 0.05).
    explanation: Transferable supernatant activity supports epithelial-stromal coupling; the responsible mediator is unresolved in the accessible abstract.
  proposed_experiments:
  - experiment_id: exp_lineage_resolved_fibrosis
    name: Lineage-resolved fibrosis with matched human spatial validation
    description: Use inducible epithelial, endothelial and stromal lineage tracing plus selective perturbations in a defined injury model; quantify lineage-labelled matrix-producing cells. Spatial human RNA/protein coexpression can validate states but must not be treated as equivalent to prospective lineage tracing.
- discussion_id: gap_human_niche_and_organoid_scope
  kind: KNOWLEDGE_GAP
  prompt: How much of the human atlas signature reflects disease, hormonal preparation or cell recovery?
  rationale: The human atlas included nine women with moderate or severe AS, five moderate and four severe, aged 34–42. AS biopsies were HRT-synchronized and obtained at least 1 cm from visible adhesions, while controls had natural cycles. Ten historical secretory controls and a twelve-sample WOI comparator overlap; they are not 22 independent controls. Recovered cell proportions, CellChat communication and RNAscope localization do not directly measure tissue-volume fractions, cell-death rates, cytokine secretion or angiogenesis. Organoids use three overlapping AS donors and three controls; P2 enrichment and XAV939 may mask differences. The paper provides no before/after cell-transplant efficacy comparison.
  attaches_to:
  - pathophysiology#Reduced Endometrial Epithelial Abundance
  - pathophysiology#Reduced WNT Communication Signature
  - pathophysiology#Reduced NOTCH Communication Signature
  evidence:
  - reference: PMID:37735465
    reference_title: Decoding the endometrial niche of Asherman's Syndrome at single-cell resolution.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: A potential confounding element in this work may arise due to the comparison of AS patients undergoing hormonal replacement therapy (HRT) cycles with control patients undergoing natural cycles
    explanation: Authors acknowledge differential hormonal exposure.
  - reference: PMID:37735465
    reference_title: Decoding the endometrial niche of Asherman's Syndrome at single-cell resolution.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: The WOI control group comprised single-cell data from six single-cell transcriptomes obtained during the WOI from the GSE111976 dataset and six endometrial samples collected during the WOI from healthy donors.
    explanation: Overlapping comparator datasets; not independent summed cohorts.
- discussion_id: gap_clinical_translation_and_adjuncts
  kind: KNOWLEDGE_GAP
  prompt: Which postoperative adjuncts improve live birth, beyond reducing visible adhesions?
  rationale: Cavity scores, recurrence, menstrual recovery, pregnancy and live birth are distinct endpoints. Some barriers reduce short-term reformation, while comparative fertility benefit remains uncertain. The newer estrogen trial in selected ovulatory women with an IUD found no significant added benefit, without proving equivalence for every regimen. A 2026 hydrogel trial improves a short-term anatomical endpoint in the adhesiolysis subgroup; this does not establish long-term fertility or molecular regeneration. Animal drug timing and species-specific exposure preclude routine T3, rapamycin or ferrostatin treatment claims.
  attaches_to:
  - pathophysiology#Intrauterine Adhesion Formation
  - pathophysiology#Reduced Receptive Endometrial Surface
  evidence:
  - reference: PMID:28603474
    reference_title: 'AAGL practice report: practice guidelines on intrauterine adhesions developed in collaboration with the European Society of Gynaecological Endoscopy (ESGE).'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Semi-solid barriers such as hyaluronic acid and auto-cross-linked hyaluronic acid gel reduce adhesion reformation. At this time, their effect on post-treatment pregnancy rates is unknown. Grade A
    explanation: The 2017 recommendation concerns adhesion reformation rather than established live-birth benefit.
  - reference: PMID:37396823
    reference_title: 'Hormonal support in women with Asherman syndrome does not lead to better outcomes: A randomized trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Of the women in usual care, 89.8% got pregnant within 3 years, and 67.8% got a living child; this was 83.6% and 60.0%, respectively, in the no-estrogen group (p = 0.33 and p = 0.39, respectively).
    explanation: Trial endpoints are nonsignificant, not proof of general equivalence.
  - reference: PMID:42492609
    reference_title: 'Safety and effectiveness of an in situ-forming hydrogel barrier in preventing intrauterine adhesions after adhesiogenic hysteroscopic procedures: a multicenter, randomized, controlled trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: 'In the adhesiolysis subgroup (n = 102), more participants in the hydrogel barrier arm were adhesion-free compared with controls (60.3% vs. 32.3%; odds ratio [OR] 3.19, 95% confidence interval [CI]: 1.29-7.90)'
    explanation: Selected subgroup with anatomical outcome and uncertainty.
  proposed_experiments:
  - experiment_id: exp_adjunct_live_birth
    name: Controlled adjunct trial with reproductive follow-up
    description: Compare well-defined postoperative regimens with standardized baseline severity, second-look assessment and subsequent live-birth follow-up. Report infertility co-factors, repeat procedures, adverse effects and subgroup uncertainty; use anatomical outcomes as intermediate endpoints rather than validated fertility surrogates.
references:
- reference: PMID:28603474
  title: 'AAGL practice report: practice guidelines on intrauterine adhesions developed in collaboration with the European Society of Gynaecological Endoscopy (ESGE).'
- reference: PMID:37735465
  title: Decoding the endometrial niche of Asherman's Syndrome at single-cell resolution.
- reference: PMID:21437822
  title: Asherman's syndrome.
- reference: PMID:39613882
  title: Mechanistic insights into intrauterine adhesions.
- reference: PMID:30713131
  title: 'Reproductive outcomes after surgical treatment of asherman syndrome: A systematic review.'
- reference: PMID:24082042
  title: 'Systematic review and meta-analysis of intrauterine adhesions after miscarriage: prevalence, risk factors and long-term reproductive outcome.'
- reference: PMID:31388435
  title: Case report of pelvic tuberculosis resulting in Asherman's syndrome and infertility.
- reference: PMID:30936754
  title: 'Asherman''s syndrome: current perspectives on diagnosis and management.'
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK448088/
  title: Asherman Syndrome - StatPearls - NCBI Bookshelf
  tags:
  - StatPearls
- reference: PMID:38493418
  title: 'Intrauterine interventions options for preventing recurrence after hysteroscopic adhesiolysis: a systematic review and network meta-analysis of randomized controlled trials.'
- reference: PMID:37396823
  title: 'Hormonal support in women with Asherman syndrome does not lead to better outcomes: A randomized trial.'
- reference: clinicaltrials:NCT05394662
  title: 'Safety and Effectiveness of Juveena™ Hydrogel System Following Transcervical Gynecologic Procedures (TCGP) At High-Risk for Intrauterine Adhesions: A Multicenter Randomized Controlled Subject and Evaluator Blinded Pivotal Study'
- reference: PMID:42492609
  title: 'Safety and effectiveness of an in situ-forming hydrogel barrier in preventing intrauterine adhesions after adhesiogenic hysteroscopic procedures: a multicenter, randomized, controlled trial.'
- reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/
  title: Defective autophagy contributes to endometrial epithelial-mesenchymal transition in intrauterine adhesions - PMC
- reference: PMID:37302615
  title: Ferroptosis contributes to endometrial fibrosis in intrauterine adhesions.
- reference: PMID:34996477
  title: 'EndMT: New findings on the origin of myofibroblasts in endometrial fibrosis of intrauterine adhesions.'
- reference: PMID:37843929
  title: Mechanisms of Regeneration and Fibrosis in the Endometrium.
📚

References & Deep Research

References

17
PMID:28603474
AAGL practice report: practice guidelines on intrauterine adhesions developed in collaboration with the European Society of Gynaecological Endoscopy (ESGE).
No top-level findings curated for this source.
PMID:37735465
Decoding the endometrial niche of Asherman's Syndrome at single-cell resolution.
No top-level findings curated for this source.
PMID:21437822
Asherman's syndrome.
No top-level findings curated for this source.
PMID:39613882
Mechanistic insights into intrauterine adhesions.
No top-level findings curated for this source.
PMID:30713131
Reproductive outcomes after surgical treatment of asherman syndrome: A systematic review.
No top-level findings curated for this source.
PMID:24082042
Systematic review and meta-analysis of intrauterine adhesions after miscarriage: prevalence, risk factors and long-term reproductive outcome.
No top-level findings curated for this source.
PMID:31388435
Case report of pelvic tuberculosis resulting in Asherman's syndrome and infertility.
No top-level findings curated for this source.
PMID:30936754
Asherman's syndrome: current perspectives on diagnosis and management.
No top-level findings curated for this source.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK448088/
Asherman Syndrome - StatPearls - NCBI Bookshelf
No top-level findings curated for this source.
PMID:38493418
Intrauterine interventions options for preventing recurrence after hysteroscopic adhesiolysis: a systematic review and network meta-analysis of randomized controlled trials.
No top-level findings curated for this source.
PMID:37396823
Hormonal support in women with Asherman syndrome does not lead to better outcomes: A randomized trial.
No top-level findings curated for this source.
clinicaltrials:NCT05394662
Safety and Effectiveness of Juveena™ Hydrogel System Following Transcervical Gynecologic Procedures (TCGP) At High-Risk for Intrauterine Adhesions: A Multicenter Randomized Controlled Subject and Evaluator Blinded Pivotal Study
No top-level findings curated for this source.
PMID:42492609
Safety and effectiveness of an in situ-forming hydrogel barrier in preventing intrauterine adhesions after adhesiogenic hysteroscopic procedures: a multicenter, randomized, controlled trial.
No top-level findings curated for this source.
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC9542425/
Defective autophagy contributes to endometrial epithelial-mesenchymal transition in intrauterine adhesions - PMC
No top-level findings curated for this source.
PMID:37302615
Ferroptosis contributes to endometrial fibrosis in intrauterine adhesions.
No top-level findings curated for this source.
PMID:34996477
EndMT: New findings on the origin of myofibroblasts in endometrial fibrosis of intrauterine adhesions.
No top-level findings curated for this source.
PMID:37843929
Mechanisms of Regeneration and Fibrosis in the Endometrium.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Review response: add DR artifact, estrogen RCT, treatment-term fixes · 2026-08-24T05:00:09Z · View source

Response to the CHANGES_REQUESTED review on PR #9239. (1) Generated the missing deep-research artifact with the claude_code provider (research/Asherman_Syndrome-deep-research-claude_code.md plus .citations.md); its built-in reference validation resolved 15/15 references with a 0.0 confabulation rate, and 'just preflight-dr' against MONDO:0015299 returned SKIP because MONDO records no causal gene for this acquired disease, so the manual gene/OMIM/synonym check was done instead and passes. (2) Cross-checked the report against the finished YAML: the one substantive omission was the randomised trial of postoperative hormonal support (PMID:37396823), now curated as REFUTE evidence on the Postoperative estrogen therapy treatment and as a new gap_postoperative_estrogen_benefit KNOWLEDGE_GAP discussion with two proposed experiments. Themes scoped out are named in the entry notes. (3) Non-blocking review suggestions: dropped the unsupported OCCASIONAL frequency band from the Recurrent pregnancy loss phenotype; bound therapeutic_agent NCIT:C280 Antitubercular Agent on the antituberculous therapy treatment (drug class rather than the four CHEBI first-line agents, because no cited source names a regimen); recorded the negative NCIT search behind the generic NCIT:C49236 binding on the intrauterine barrier device. Validation: 'just validate' reports 55/55 snippets verified, and validate-terms, check-duplicate-keys, check-folded-hyphens, check-snippet-length and check-title-snippets all pass.

Claude Code ▸
1. Disease Information
claude-haiku-4-5-20251001, claude-opus-4-8[1m] 19 citations 2026-08-24T04:51:10.252259

1. Disease Information

Overview. Asherman syndrome is a rare, acquired gynecological disorder characterized by the formation of intrauterine adhesions (IUA) / synechiae — fibrous scar tissue that partially or completely obliterates the uterine cavity and/or cervical canal. It arises from damage to the basal (regenerative) layer of the endometrium, most often after intrauterine instrumentation, leading to non-regenerative healing in which functional endometrium is replaced by fibrous connective tissue and opposing uterine walls adhere. The clinical triad is menstrual abnormality (hypomenorrhea/amenorrhea), infertility/recurrent pregnancy loss, and cyclic pelvic pain. The eponym honors Joseph Asherman, who characterized the syndrome in 1948–1950.

A useful nomenclature distinction (increasingly emphasized in the literature): "intrauterine adhesions" is the anatomical/hysteroscopic finding, whereas "Asherman syndrome" is reserved for IUA accompanied by symptoms (menstrual disturbance, infertility, pain). In one retrospective cohort, of patients with adhesions, 76.1% were classified as IUA and 23.9% met criteria for symptomatic Asherman syndrome (PMID:40310333).

Key identifiers: - MONDO: MONDO:0015299 - Orphanet: ORPHA:137686 - ICD-10: N85.6 (Intrauterine synechiae) - ICD-11: GA20 (Non-inflammatory disorders of the uterus) / relevant synechiae code - MeSH: "Gynatresia" / "Asherman Syndrome" is indexed under MeSH term D054882 (Gynatresia); IUA also indexed under uterine diseases - OMIM: Not applicable (acquired, non-Mendelian) - NORD: Listed rare disease profile (NORD)

Synonyms / alternative names: Intrauterine adhesions; intrauterine synechiae; uterine synechiae; endometrial sclerosis; sclerotic endometrium; traumatic uterine atrophy; uterine/cervical atresia (older usage); Asherman's syndrome. (NORD, Orphanet)

Data derivation: Disease-level knowledge is aggregated from case series, retrospective cohorts, hysteroscopy registries, and increasingly from single-cell molecular atlases of patient endometrium — not from a single population EHR resource. It is under-captured in administrative datasets because many cases are diagnosed only at hysteroscopy during infertility work-up.

2. Etiology

Primary causal mechanism — endometrial basalis trauma. The dominant cause (>90% of cases) is iatrogenic mechanical injury to the endometrial basal layer, typically in a hormonally hypoestrogenic, recently pregnant uterus where the endometrium is thin and vulnerable (PMID:40310333).

Disease causal factors / procedures: - Dilation and curettage (D&C) for miscarriage or retained products of conception (RPOC) — the single most common cause; up to ~40% of women undergoing D&C for RPOC develop adhesions (management review, Springer). - Postpartum curettage — IUA in ~22% (PMID:40310333). - Termination of pregnancy (TOP) — first-trimester ~21.2%; second-trimester 16.2–21% (PMID:40310333). - Myomectomy — ~9.3% incidence, especially with cavity entry (PMID:40310333). - Cesarean section, B-Lynch compression suturing, uterine artery embolization, and other conservative postpartum-hemorrhage interventions. - Infectious / inflammatory causes: genital tuberculosis (a leading cause in endemic regions, often producing severe disease), schistosomiasis, chronic endometritis, and pelvic inflammatory disease. - Congenital predisposition: Müllerian anomalies — one series found 31.6% of septate uteri developed IUAs (PMID:40310333).

Risk factors (environmental / clinical): - Timing of curettage is the most consistent modifiable risk factor: all women who developed IUA in one post-abortion cohort had undergone curettage 8–28 days after delivery/miscarriage, with 75% in the 14–24-day window (Identifying risk factors and incidence, PMID:33462894). Elevated risk persists up to ~4 weeks post-delivery/miscarriage. - Repeated uterine instrumentation / repeat abortions — the principal risk factor; risk rises with number of procedures. - Negative uterine (suction) pressure — extremely strong association (OR 125.61, 95% CI 67.35–183.87) (PMID:40310333). - Chronic endometritis — present in 64.3% of severe cases (PMID:40310333). - Age >35 years (confounded by cumulative prior procedures); low estrogen state.

Genetic risk factors: None established as causal. AS is acquired. There may be individual variation in fibrotic/wound-healing propensity (e.g., TGF-β pathway polymorphisms), but no validated susceptibility locus, GWAS signal, or ClinVar entry exists for AS. Not Applicable / Not established.

Protective factors: The strongest protective strategy is avoiding sharp curettage in favor of medical management (misoprostol) or ultrasound-guided gentle suction/manual vacuum aspiration, and avoiding the high-risk 2–4 week postpartum window (Fertility & Sterility, uterine evacuation approach). No genetic protective variants are known.

Gene–environment interactions: Not characterized for AS. Host fibrotic response to endometrial injury is the plausible interaction axis but is unproven.

3. Phenotypes

Phenotype Type Suggested HPO Frequency / notes
Amenorrhea / hypomenorrhea Menstrual sign HP:0000141 (Amenorrhea); HP:0011225 (Hypomenorrhea) Amenorrhea in 34.4% of AS vs 2.0% of IUA (OR 26.19); hallmark of severe disease (PMID:40310333)
Female infertility Reproductive sign HP:0008222 (Female infertility) Very frequent; a leading cause of refractory uterine-factor infertility
Recurrent pregnancy loss Reproductive sign HP:0100615 / HP:0500110 (Recurrent spontaneous abortion) 5–39% of women with recurrent miscarriage have IUA (Springer review)
Cyclic pelvic pain / dysmenorrhea Symptom HP:0002360 (dysmenorrhea-related); HP:0012531 (Pain) Dysmenorrhea 43.8% in AS vs 22.5% IUA; from trapped menstrual blood (hematometra) behind cervical obstruction
Hematometra Physical manifestation HP:0030144 (Hematometra) Occurs when outflow is obstructed by cervical/lower-segment adhesions
Abnormal uterine cavity / synechiae Imaging finding HP:0031331 (Abnormal uterine morphology) Defining hysteroscopic finding
Placenta accreta spectrum (obstetric complication) Physical manifestation HP:0011409 (Abnormal placenta morphology) Increased in subsequent pregnancies due to deficient decidualization

Characteristics: - Age of onset: Reproductive-age adult; onset is temporally linked to the inciting procedure (mean age ~33 years in cohorts; onset days-to-weeks after instrumentation) (PMID:40310333). - Severity: Variable — graded mild/moderate/severe. AS cohorts skew severe (58.1% AFS stage III) vs IUA cohorts skewing mild (54.9% AFS stage I) (PMID:40310333). - Progression: Chronic and, without treatment, stable-to-progressive; adhesions can re-form aggressively after lysis (severe cases up to 62.5% recurrence, see §11). - QoL impact: Substantial — infertility, pregnancy loss, chronic cyclic pain, and psychological distress; measured with general instruments (SF-36/EQ-5D) rather than AS-specific tools.

4. Genetic / Molecular Information

Causal genes: None. Asherman syndrome is an acquired fibrotic disorder with no Mendelian gene, no pathogenic germline variant, and no OMIM entry. ClinVar/HGMD/COSMIC are Not Applicable.

Molecularly dysregulated genes (acquired expression changes, not mutations) — from single-cell and expression studies: - TGFB1 (TGF-β1) — up-regulated; central pro-fibrotic driver via SMAD2/3 signaling, promoting myofibroblast differentiation (single-cell review searches). - ACTA2 (α-SMA) and COL1A1 (collagen I) — up-regulated myofibroblast/ECM markers. - THBS1 (thrombospondin-1) — identified as a key pro-fibrotic factor modulating PI3K/AKT, and a stem-cell-reversible target (Frontiers, THBS1). - SLPI (secretory leukocyte protease inhibitor) — marks a stressed epithelial subpopulation characteristic of AS during the implantation window (Nat Commun single-cell atlas, PMID:37735465). - WNT7A / FZD6 / LRP6 — loss of ligand–receptor communication (impaired epithelial differentiation). - JAG1 / NOTCH2 — decreased communication affecting glandular differentiation. - IGFBP3/5/6 — up-regulated anti-angiogenic factors. - Stress-response genes HSPA1A, SOCS3 co-expressed in the stressed epithelium.

Suggested HGNC/gene annotations: TGFB1 (hgnc:11766), ACTA2 (hgnc:130), COL1A1 (hgnc:2197), THBS1 (hgnc:11785), SLPI (hgnc:11092), WNT7A (hgnc:12786), NOTCH2 (hgnc:7882).

Epigenetics: Emerging evidence implicates altered DNA methylation and non-coding RNAs (various miRNAs regulating TGF-β/Smad and EMT) in endometrial fibrosis, but this remains preliminary and not part of routine characterization.

Chromosomal abnormalities: Not applicable.

5. Environmental Information

  • Environmental / occupational toxins: No established chemical or radiation etiology (external pelvic radiation could theoretically damage endometrium, but is not a recognized AS cause).
  • Lifestyle factors: No direct causal lifestyle factors; the operative risk is procedural, not behavioral.
  • Infectious agents (can trigger/cause):
  • Mycobacterium tuberculosis (NCBITaxon:1773) — genital tuberculosis is a major cause of severe AS in endemic regions.
  • Schistosoma spp. — genital schistosomiasis (regional).
  • Polymicrobial chronic endometritis and PID organisms contribute to the inflammatory/fibrotic milieu.

6. Mechanism / Pathophysiology

Causal chain (upstream → downstream):

  1. Trauma to endometrial basalis (curettage, especially on gravid/postpartum uterus) → loss of the regenerative stem/progenitor niche.
  2. Local ischemia and inflammation → hypoxic, pro-inflammatory microenvironment (increased macrophages, B cells, dendritic cells on single-cell profiling).
  3. TGF-β1 → SMAD2/3 activation → fibroblast-to-myofibroblast transdifferentiation (↑α-SMA), with contributions from CXCR4 signaling and THBS1/PI3K-AKT (TGF-β/Smad2/3 in IUA).
  4. Excessive ECM deposition — collagen I, laminin, fibronectin (FN1) from stromal fibroblasts; single-cell data show "a shift from epithelial–stromal interactions to ECM-based self-stromal signaling" (PMID:37735465).
  5. Failed epithelial regeneration — dramatic epithelial loss (8.3% vs 51.65% of cells) and near-absent ciliated epithelium (0.19% vs 5.3%), with disrupted WNT (loss of WNT7A–FZD6/LRP6) and NOTCH (↓JAG1–NOTCH2) signaling impairing differentiation (PMID:37735465).
  6. Anti-angiogenic environment — up-regulated IGFBP3/5/6 → poor revascularization → perpetuates ischemia (a self-reinforcing fibrotic loop).
  7. Adhesion formation — opposing fibrotic walls fuse; cavity/cervical obliteration.
  8. Clinical manifestation — reduced functional endometrium → hypomenorrhea/amenorrhea, impaired implantation/decidualization → infertility, RPL, placenta accreta spectrum.

Cellular processes / GO terms: - Wound healing / fibrosis: GO:0061041 (regulation of wound healing), GO:0030198 (ECM organization) - TGF-β receptor signaling: GO:0007179 - Myofibroblast differentiation / fibroblast activation - Inflammatory response: GO:0006954 - Epithelial cell differentiation: GO:0030855 (disrupted) - Angiogenesis: GO:0001525 (suppressed) - Wnt signaling: GO:0016055; Notch signaling: GO:0007219

Cell types involved (CL terms): - Endometrial stromal fibroblast → myofibroblast (CL:0000186) — the fibrogenic effector - Endometrial (luminal/glandular) epithelial cell (CL:0002586 / CL:0000066) — lost/stressed - Ciliated epithelial cell (CL:0000064) — markedly depleted - Macrophage (CL:0000235), B cell (CL:0000236), dendritic cell (CL:0000451) — expanded - Vascular endothelial cell (CL:0000115) — anti-angiogenic shift

Molecular profiling available: Single-cell RNA-seq atlas of AS endometrium (PMID:37735465; medRxiv preprint 2022) is the flagship dataset, defining the SLPI+ stressed epithelium and the pro-fibrotic/anti-angiogenic niche. This is the strongest candidate dataset for KB datasets: linkage (GEO deposition associated with the Nature Communications paper).

7. Anatomical Structures Affected

  • Primary organ: Uterus (UBERON:0000995), specifically the endometrium (UBERON:0001295) and its basal layer.
  • Tissue level: endometrial epithelium (glandular + luminal), endometrial stroma, uterine cavity; fibrous scar replacing functional mucosa.
  • Secondary sites: cervix / cervical canal / internal os (UBERON:0000002) — obstruction here causes hematometra; fallopian tube ostia may be occluded, contributing to infertility.
  • Subcellular/GO cellular component: ECM (extracellular region, GO:0005576); collagen-containing ECM (GO:0062023).
  • Body system: Female reproductive system (UBERON:0000474).
  • Lateralization: Adhesions are distributed within the cavity (may be marginal, central, or diffuse); disease is of a single midline organ — not lateralized per se.

8. Temporal Development

  • Onset: Adult, reproductive age; acquired, temporally linked to instrumentation (days–weeks after the inciting procedure). Onset pattern is subacute (fibrosis develops over the healing window).
  • Progression stages: Graded mild → moderate → severe by cavity involvement and adhesion density (see classification, §10). Severe disease features dense, cavity-obliterating adhesions and amenorrhea.
  • Course: Chronic; without intervention, stable-to-progressive. Post-treatment recurrence is the defining temporal problem — reformation of adhesions after lysis, up to 62.5% in severe disease.
  • Critical intervention windows: (a) Prevention window — the 2–4 week postpartum/post-miscarriage period when curettage is most dangerous; (b) Post-adhesiolysis window — early second-look hysteroscopy and barrier/estrogen measures to prevent reformation.

9. Inheritance and Population

  • Inheritance: Not applicable — acquired, non-heritable. No penetrance, expressivity, anticipation, mosaicism, founder effect, consanguinity, or carrier-frequency considerations.
  • Epidemiology: True population prevalence is uncertain (under-diagnosed). Procedure-conditioned incidence:
  • 16–45.5% of women develop IUA after intrauterine interventions (miscarriage management, TOP, D&C) (PMID:40310333).
  • Up to ~21.5% after D&C generally; up to ~40% after D&C for RPOC.
  • ~1.5% of women undergoing HSG show IUA; 5–39% of women with recurrent miscarriage (Springer review).
  • Orphanet lists it as a rare disease.
  • Population demographics: Affects women of reproductive age worldwide; higher burden in regions with high rates of unsafe abortion, postpartum curettage, and genital tuberculosis (parts of South Asia, Africa). Sex: exclusively female (uterine organ). Mean age in cohorts ~33 years.

10. Diagnostics

Gold standard: Hysteroscopy — direct visualization of the cavity, permitting simultaneous diagnosis and treatment (Dovepress current perspectives, PMID:30936754; PMID:40310333).

Imaging / functional tests: - 3D transvaginal ultrasound (TVUS): sensitivity 98.8%, specificity 90.8%, accuracy 91.4% (PMID:40310333); useful first-line/screening; can assess endometrial thickness. - Saline infusion sonohysterography (SIS): less invasive cavity assessment. - Hysterosalpingography (HSG): shows filling defects but limited accuracy (~50%); also assesses tubal patency (PMID:40310333). - MRI: reserved for totally obliterated cavities where hysteroscopy cannot access the fundus. - Laboratory / endocrine: used to exclude other causes of amenorrhea (FSH, estradiol, prolactin, TSH, hCG) — endocrine axis is typically normal in AS, distinguishing it from ovarian/hypothalamic causes.

Classification systems: No universally validated system; ~7 exist. Most used: - American Fertility Society (AFS, 1988) scoring (extent of cavity, adhesion type, menstrual pattern) → stages I (mild), II (moderate), III (severe). - ESGE (European Society for Gynaecological Endoscopy) classification. - Nasr et al. (2000) clinicohysteroscopic score.

Differential diagnosis: Hypothalamic amenorrhea, premature ovarian insufficiency, PCOS, pregnancy, endometrial atrophy, cervical stenosis, Müllerian agenesis — distinguished by normal endocrine profile plus cavity findings on imaging/hysteroscopy.

Genetic testing: Not applicable.

11. Outcome / Prognosis

  • Reproductive outcomes after hysteroscopic adhesiolysis: In a treated cohort, cumulative pregnancy rate 81.9% and cumulative live birth rate 51.2%, with outcomes stratifying by severity (low-resource setting review, PMC10848492). Milder disease has far better prognosis: AFS stage I ~>75% fertility prognosis; stage III often 25–50% (PMID:40310333).
  • Recurrence: The central prognostic obstacle. Adhesion reformation correlates with baseline severity; severe IUA recurrence up to 62.5% (outcomes searches).
  • Obstetric complications in achieved pregnancies: increased placenta accreta spectrum, placenta previa, preterm birth, IUGR, and miscarriage, owing to deficient decidualization over scarred segments.
  • Mortality: AS is not directly life-threatening; morbidity is reproductive (infertility, pregnancy loss) and quality-of-life (chronic pain, psychological burden). Rare severe placenta accreta in subsequent pregnancy carries hemorrhage risk.
  • Prognostic factors: severity/AFS stage, extent of residual functional endometrium, endometrial thickness/vascularity post-treatment, presence of chronic endometritis, and adhesion density.

12. Treatment

Standard of care — hysteroscopic adhesiolysis (NCIT:C15329 Surgical Procedure; more specifically operative hysteroscopy): - Cold microscissors preferred over electrosurgery to reduce thermal injury, perforation, and recurrence (outcomes searches). - Severe/obliterated cases may need ultrasound- or laparoscopy-guided dissection; often repeated procedures.

Post-operative adhesion-reformation prevention (adjuncts — the key strategy given high recurrence): - Physical barriers: intrauterine balloon (Foley/Cook), IUD, hyaluronic acid gel / auto–cross-linked HA (NCT02617108; HA outcomes PMID:41267665). - Hormonal (estrogen ± progestogen) therapy to stimulate re-epithelialization (NCIT:C15986 Pharmacotherapy; therapeutic_agent estrogen, CHEBI). Important recent evidence caveat: a randomized trial (Hanstede et al., 2023, PMID:37396823) found hormonal support did NOT improve recurrence, menses, or endometrial thickness — the efficacy of routine post-adhesiolysis estrogen is now questioned. Curate this as a KNOWLEDGE_GAP / competing-evidence point rather than settled benefit. - Antibiotics where chronic endometritis is present. - Platelet-rich plasma (PRP) intrauterine infusion — emerging adjunct.

Advanced / experimental (regenerative) therapeutics (NCIT:C15238 Gene Therapy / NCIT:C15431 stem-cell / cell therapy): - Menstrual blood-derived mesenchymal stem cells (MenSCs) — attenuate TGF-β, down-regulate α-SMA and collagen I, promote proliferation; act mainly via paracrine signaling (PMID:30760192; MenSC review). - Bone marrow / umbilical cord MSCs, autologous stem cell mobilization. - Stem-cell–derived exosomes and bioengineered hydrogels/scaffolds; hESC-derived endometrial organoids + 3D Matrigel (PMC8079828). - Molecular targets under study: THBS1 (PI3K/AKT), TGF-β1/Smad2/3 axis. - Assisted reproduction: IVF ± gestational surrogacy for refractory uterine-factor infertility.

Pharmacogenomics: Not applicable.

13. Prevention

  • Primary prevention (most impactful):
  • Avoid unnecessary curettage; prefer medical management (misoprostol) or expectant management for miscarriage.
  • Use ultrasound-guided gentle suction / manual vacuum aspiration rather than sharp curettage.
  • Avoid the 2–4 week postpartum/post-miscarriage high-risk window for instrumentation (Fertility & Sterility; PMID:33462894).
  • Limit repeat intrauterine procedures; treat genital infections (including TB) promptly.
  • Secondary prevention: early hysteroscopic diagnosis in women with post-procedure menstrual change or infertility; treat chronic endometritis.
  • Tertiary prevention: post-adhesiolysis barriers (balloon/HA gel), early second-look hysteroscopy to lyse re-forming adhesions, and endometrial-regeneration adjuncts.
  • Counseling: reproductive/pre-conception counseling; genetic counseling not applicable.

14. Other Species / Natural Disease

  • Taxonomy: Human disease (Homo sapiens, NCBITaxon:9606). Naturally occurring analogous intrauterine adhesion disease in other species is not well documented; endometrial fibrosis/scarring can occur in domestic animals but "Asherman syndrome" is a human clinical entity.
  • Breed / OMIA / veterinary: No established OMIA entry (acquired, not genetic).
  • Comparative biology: Endometrial regeneration is a conserved mammalian process; rodents serve as mechanistic surrogates rather than natural-disease models.
  • Zoonosis / transmission: Not applicable.

15. Model Organisms

  • Rodent (mouse/rat) mechanical/chemical injury models — the workhorse: Induced by intrauterine curettage/scraping, electrocoagulation, ethanol/trichloroacetic-acid instillation, or dual mechanical+LPS injury. These recapitulate endometrial fibrosis, ↑TGF-β1/Smad, ↑α-SMA/collagen, thinned endometrium, and impaired fertility, and are the standard platform for testing MSC/exosome/hydrogel therapies (mechanisms & stem cell therapy review).
  • In vitro / cellular models: primary human endometrial stromal cells with TGF-β1 stimulation (fibrosis induction); endometrial epithelial cultures; iPSC/hESC-derived endometrial organoids (PMC8079828).
  • Model characteristics / limitations: Rodent uterine anatomy (bicornuate, rapid estrous cycling, high regenerative capacity) differs from human; models capture fibrosis and functional infertility well but imperfectly reproduce the human implantation-window epithelial phenotype and chronic recurrence dynamics. evidence_source: MODEL_ORGANISM for all rodent data; IN_VITRO for organoid/cell work.
  • Resources: No dedicated AS model repository; models are protocol-defined and reported ad hoc in the literature.

Key Ontology Term Summary (for KB population)

  • MONDO: MONDO:0015299 (Asherman syndrome)
  • Phenotypes (HP): HP:0000141 (Amenorrhea), HP:0011225 (Hypomenorrhea), HP:0008222 (Female infertility), HP:0500110/HP:0100615 (Recurrent spontaneous abortion), HP:0030144 (Hematometra), HP:0031331 (Abnormal uterine morphology)
  • Anatomy (UBERON): UBERON:0001295 (endometrium), UBERON:0000995 (uterus), UBERON:0000002 (cervix), UBERON:0000474 (female reproductive system)
  • Cells (CL): CL:0000186 (myofibroblast), CL:0000066 (epithelial cell), CL:0000064 (ciliated cell), CL:0000235 (macrophage)
  • Processes (GO): GO:0007179 (TGF-β receptor signaling), GO:0030198 (ECM organization), GO:0061041 (regulation of wound healing), GO:0001525 (angiogenesis), GO:0016055 (Wnt signaling)
  • Treatments (NCIT): NCIT:C15329 (Surgical Procedure — hysteroscopic adhesiolysis), NCIT:C15986 (Pharmacotherapy — estrogen), NCIT:C15238 (Gene Therapy), cell therapy (MSC)

Curation Caveats / Evidence Notes

  1. Acquired disease — do not populate causal-gene, inheritance, or germline-variant slots; explicitly mark N/A.
  2. Hormonal support efficacy is contested — the 2023 RCT (PMID:37396823) is a REFUTE/PARTIAL-type evidence item against routine post-op estrogen; curate as a knowledge gap.
  3. Single-cell atlas (PMID:37735465) is the strongest molecular source for pathophysiology nodes and has an associated GEO dataset worth linking.
  4. Verify all PMIDs and snippets with just fetch-reference before committing — PubMed abstracts were partly cookie-walled during this research; the exact-quote SOP (§Adding Evidence) must be applied to each claim.
  5. This entry is a strong candidate to conforms_to the fibrotic_response module (tissue injury → inflammation → myofibroblast activation → excessive ECM → organ dysfunction), substituting endometrial stromal fibroblast → myofibroblast.

Sources

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 15
Resolved 15
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 15
On topic 9
Off topic 0

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