Asherman_Syndrome

Acquired MONDO:0015299 Pathograph 15 Show in embeddings browser uterine disease endometrium disease

Asherman syndrome is an acquired fibrotic disease of the uterine cavity in which the basal (regenerative) layer of the endometrium is destroyed, most often by curettage of the pregnant or recently pregnant uterus, and the endometrium heals by scarring instead of regenerating. The scar tissue bridges the opposing walls of the cavity as intrauterine adhesions, partially or completely obliterating the cavity and the cervical canal. Clinically it presents with hypomenorrhea or amenorrhea, cyclic pelvic pain from outflow obstruction, infertility, and recurrent pregnancy loss. What makes the disease mechanistically interesting is that it is a regeneration failure in a tissue that is otherwise an exemplar of scarless repair: the endometrium is shed and rebuilt without scarring dozens of times across the reproductive lifespan, and after parturition sheds a substantial portion of the tissue, yet after certain iatrogenic insults the same tissue scars. The entry therefore models the disease as a switch between two repair programmes rather than as fibrosis added on top of normal healing, and it conforms to the `fibrotic_response` module along the conserved injury-inflammation-myofibroblast-ECM chain while keeping the endometrium-specific epithelial-loss arm — described at single-cell resolution in human Asherman endometrium — as its own node. Three amplifier mechanisms (defective autophagy, ferroptosis, and endothelial-to-mesenchymal transition) are curated as EMERGING hypotheses rather than asserted on the canonical chain, because each rests on patient tissue plus rodent or in vitro perturbation rather than on human interventional evidence.

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10
Pathophys.
7
Phenotypes
4
Hypotheses
4
Gaps
15
Pathograph
5
Medical Actions
3
Differentials
1
Deep Research
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Classifications

Harrison's Part
ENDOCRINOLOGY METABOLISM
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Mechanistic Hypotheses

4
Basalis destruction switches endometrial repair from regeneration to scarring
nonregenerative_fibrotic_repair CANONICAL
Evidence balance 1 support
The accepted account. Injury that removes or destroys the endometrial basal layer eliminates the regenerative compartment from which the functionalis is normally rebuilt. Repair then proceeds by the generic fibrotic route — inflammation, myofibroblast generation, collagen deposition — and the resulting fibrous connective tissue replaces endometrium rather than being remodelled away. Because the injury is typically to opposing surfaces of a collapsed cavity, the scar bridges them, producing adhesions rather than simple mural fibrosis.
Show evidence (1 reference)
PMID:39613882 SUPPORT Human Clinical
"Intrauterine adhesions (IUA), also known as Asherman's syndrome, arise from damage to the basal layer of the endometrium, frequently caused by intrauterine interventions. This damage leads to nonregenerative healing of endometrium resulting in replacement by fibrous connective tissue"
States the canonical chain in one sentence: basalis damage, then nonregenerative healing, then fibrous replacement.
Defective epithelial autophagy (DIO2-MAPK/ERK-MTOR) drives epithelial-mesenchymal transition
autophagy_defect_emt EMERGING
Evidence balance 1 support
Autophagy is defective in the endometrium of Asherman patients and is associated with DIO2 downregulation. In endometrial epithelial cells, blocking autophagy pharmacologically promotes EMT and enhancing it with rapamycin attenuates EMT; silencing DIO2 blocks autophagic flux and drives EMT through MAPK/ERK-MTOR. The patient observation is correlative and every causal step is cell-culture or mouse, so this is curated as an amplifier hypothesis rather than as part of the canonical chain.
Pathograph links
Endometrial Epithelial Loss and Differentiation Signalling Failure -> Myofibroblast Generation and Mesenchymal Activation DIRECT Epithelial cells that undergo epithelial-mesenchymal transition, rather than being replaced, contribute directly to the myofibroblast pool. Both the autophagy-defect and ferroptosis hypotheses act on this edge, and both were demonstrated on the epithelial compartment specifically.
Defective Epithelial Autophagy -> Endometrial Epithelial Loss and Differentiation Signalling Failure DIRECT Loss of autophagic flux destabilizes epithelial homeostasis and pushes epithelial cells toward a mesenchymal phenotype.
Show evidence (1 reference)
PMID:35196191 SUPPORT In Vitro
"we demonstrated that autophagy is defective in endometria of IUA patients, which aggravates EMT and endometrial fibrosis, and defective autophagy is related to DIO2 (iodothyronine deiodinase 2) downregulation"
States the hypothesis and names the DIO2 link. Classified IN_VITRO because the causal demonstrations in this paper are in endometrial epithelial cell culture; the patient data are descriptive.
Increased ferroptosis load in injured endometrium amplifies epithelial EMT and fibrosis
ferroptosis_amplification EMERGING
Evidence balance 2 support
RNA-seq of severe Asherman endometrium against normal controls found an increased ferroptosis load, and erastin-induced ferroptosis promoted EMT and fibrosis in endometrial epithelial cells while the ferroptosis inhibitor ferrostatin-1 ameliorated fibrosis in a dual-injury murine model. The compartment specificity matters and is preserved here: erastin did not produce pro-fibrotic differentiation in endometrial stromal cells directly, so the proposed route runs through the epithelium.
Pathograph links
Endometrial Epithelial Loss and Differentiation Signalling Failure -> Myofibroblast Generation and Mesenchymal Activation DIRECT Epithelial cells that undergo epithelial-mesenchymal transition, rather than being replaced, contribute directly to the myofibroblast pool. Both the autophagy-defect and ferroptosis hypotheses act on this edge, and both were demonstrated on the epithelial compartment specifically.
Endometrial Ferroptosis -> Endometrial Epithelial Loss and Differentiation Signalling Failure DIRECT Ferroptotic death and stress in the epithelial compartment promote epithelial-mesenchymal transition and epithelial loss.
Show evidence (2 references)
PMID:37302615 SUPPORT In Vitro
"we demonstrated that ferroptosis load is increased in IUA endometria. In vitro experiments showed that erastin-induced ferroptosis promoted EMT and fibrosis in endometrial epithelial cells"
Establishes the patient-tissue observation and the in vitro causal step this hypothesis rests on.
PMID:37302615 SUPPORT In Vitro
"but did not lead to pro-fibrotic differentiation in endometrial stromal cells (HESCs)"
Retained as a deliberate negative limit on the hypothesis: the ferroptotic stimulus does not act directly on the stromal compartment, which is why the hypothesis is wired through the epithelial node and not the myofibroblast node.
Endothelial-to-mesenchymal transition contributes myofibroblasts to endometrial fibrosis
endmt_myofibroblast_origin EMERGING
Evidence balance 1 support
A rat intrauterine adhesion model showed cells doubly positive for the endothelial marker CD31 and the myofibroblast marker alpha-SMA in the endometrium 14 days after injury, with falling CD31 and rising alpha-SMA and vimentin, implicating endothelium as one source of the myofibroblast pool. No human confirmation was found in this curation pass, so the arm is EMERGING and carries a HUMAN_MODEL_MISMATCH discussion.
Show evidence (1 reference)
PMID:34996477 SUPPORT 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."
The dual-marker observation on which the EndMT origin claim rests, in a rat model.
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Discussions and Knowledge Gaps

4
Does endothelial-to-mesenchymal transition contribute to the myofibroblast pool in human Asherman syndrome, or is it a feature of the rat mechanical-injury model?
HUMAN MODEL MISMATCH mismatch_endmt_rat_model_only
Attached to
pathophysiology#Myofibroblast Generation and Mesenchymal Activation
The EndMT arm rests entirely on a rat intrauterine adhesion model, where CD31/alpha-SMA double-positive cells appear in endometrium 14 days after injury. No human tissue confirmation was found in this curation pass. The mismatch is mechanistically meaningful rather than cosmetic: the human single-cell atlas of Asherman endometrium characterizes the disease niche in detail and emphasizes epithelial loss, so if EndMT were a major human myofibroblast source it might be expected to have surfaced there. Rodent IUA models are also made by acute mechanical or dual injury, which may recruit vascular remodelling responses that the slower human iatrogenic lesion does not.
Proposed experiments
Lineage-resolved myofibroblast origin in human Asherman endometrium
exp_ias_human_myofibroblast_origin
Re-analyse or extend human Asherman single-cell/single-nucleus datasets for endothelial-mesenchymal intermediate states, and confirm with dual CD31/alpha-SMA immunofluorescence on Asherman hysteroscopic biopsies against matched controls, to quantify what fraction of the myofibroblast pool is endothelium-derived in human disease.
Why does the endometrium regenerate without scarring after menstruation and parturition, yet scar after curettage of the recently pregnant uterus?
KNOWLEDGE GAP gap_regeneration_versus_scarring_switch
Attached to
pathophysiology#Non-Regenerative Fibrotic Repair and Excessive ECM Deposition
This is the central unanswered question of the disease and the reason the entry is modelled as a switch between repair programmes. The endometrium is an exemplar of scarless mammalian regeneration, including after the substantial tissue loss of childbirth, yet a comparatively minor iatrogenic insult in the same postpartum window produces permanent scar. Neither the depth of injury nor the pregnant state alone accounts for it, and identifying the determinant would be informative well beyond gynaecology — it is the question the regeneration literature explicitly poses of this tissue.
Proposed experiments
Paired injury-response profiling across regenerative and scarring insults
exp_ias_paired_injury_response_profiling
Profile the endometrial repair response after physiological shedding, postpartum involution, and instrumental evacuation in the same species and pregnancy state, to identify the divergence point at which the fibrotic programme is selected over the regenerative one.
Show evidence (1 reference)
PMID:37843929 SUPPORT Human Clinical
"Thus, the endometrium provides an exceptional platform to answer a central question of regenerative medicine: Why do some systems regenerate while others scar?"
The review poses this gap as an open question in exactly the terms used here, which is why it is recorded as a KNOWLEDGE_GAP rather than curated as a mechanism.
Can reproductive prognosis after adhesiolysis be predicted, and can recurrence be prevented?
KNOWLEDGE GAP gap_prognosis_and_recurrence_prevention
Attached to
pathophysiology#Intrauterine Adhesion Formation and Cavity Obliteration
Two related failures of the current standard of care. There is no established method for predicting the likelihood of a live birth after treatment, and no adjunct has been shown superior for preventing adhesion reformation — which is the principal clinical problem, since recurrence rather than initial division is what limits outcomes. Both are recorded here because the treatment block would otherwise read as more settled than it is.
Proposed experiments
Prospective prognostic model for live birth after adhesiolysis
exp_ias_live_birth_prognostic_model
Assemble a prospective multicentre cohort with standardized severity grading, residual endometrial thickness and second-look hysteroscopy, and derive and externally validate a live-birth prediction model.
Head-to-head randomized comparison of anti-adhesion adjuncts
exp_ias_anti_adhesion_adjunct_rct
Randomize balloon stent, intrauterine device, hyaluronic acid gel and no adjunct after adhesiolysis, with second-look hysteroscopy as the primary endpoint and live birth as a secondary endpoint.
Show evidence (2 references)
PMID:39613882 SUPPORT Human Clinical
"Classical treatments have shown limited success, particularly in severe cases."
The review's own assessment of current treatment. Its adjacent sentence on the prognostic gap is quoted here only in the rationale, because as published it reads "remains established" where the sense requires "unestablished", and an evidence snippet should not carry a claim whose literal wording contradicts it.
PMID:28582327 SUPPORT Human Clinical
"Prevention of reformation of adhesions remains challenging and no single method for preventing recurrence has shown superiority."
Independent statement of the recurrence-prevention half of this gap.
Does postoperative estrogen actually improve outcomes after adhesiolysis, and if the mechanism is real, why does the trial not detect a benefit?
KNOWLEDGE GAP gap_postoperative_estrogen_benefit
Attached to
pathophysiology#Endometrial Epithelial Loss and Differentiation Signalling Failure
Postoperative estrogen is the one element of the standard regimen aimed at the regenerative failure rather than at the scar, and it is given on an explicit mechanistic rationale — drive proliferation of surviving endometrium across the denuded cavity. A randomised trial that simply withheld it found no increase in adhesion recurrence and no reduction in pregnancy or live-birth rates, while noting side effects. That is a gap rather than a settled negative: at least three readings remain open and the trial does not separate them. The regenerative substrate may be absent in the patients who most need it, so a proliferative drug has nothing to act on; the endogenous cycling estrogen of an ovulatory cohort may already saturate the receptor, leaving exogenous estrogen no margin; or epithelial proliferation may simply not be rate-limiting for the outcomes measured, which are dominated by recurrence of fibrosis. Recording it keeps the entry from presenting a contested adjunct as established care, and keeps the mechanism curated at the strength the evidence supports — plausible pharmacology, unproven benefit.
Proposed experiments
Estrogen benefit stratified by residual functional endometrium
exp_ias_estrogen_stratified_by_residual_endometrium
Re-randomize or re-analyse post-adhesiolysis estrogen against no estrogen with patients stratified by residual endometrial thickness and by whether any basalis is identifiable at second-look hysteroscopy, to test whether a proliferative agent benefits only the subgroup that retains a substrate for it to act on.
Direct measurement of endometrial target engagement under estrogen
exp_ias_estrogen_target_engagement
Measure proliferation directly (endometrial thickness on serial ultrasound, Ki-67 index on second-look biopsy) in treated versus untreated arms, to establish whether the proliferative mechanism engages at all in this setting before attributing the null outcome result to it.
Show evidence (1 reference)
PMID:37396823 SUPPORT Human Clinical
"Usual care does not lead to better outcomes as compared with not giving exogenous estrogen but is associated with side effects."
The trial's own conclusion, which is what opens the gap. It is cited as SUPPORT for the *existence* of the gap here, and separately as REFUTE against the benefit claim on the estrogen treatment entry.
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Pathophysiology

10
Endometrial Basal Layer Injury
The initiating lesion. Instrumentation of the pregnant or recently pregnant uterus — classically sharp curettage after miscarriage or postpartum — strips or destroys the basal layer of the endometrium, the compartment that regenerates the functionalis after each shedding. Hysteroscopic surgery, uterine artery embolization and uterine tuberculosis produce the same lesion by different routes. The gravid or recently gravid state is the important modifier: the same instrument used on a non-pregnant uterus is far less likely to cause adhesions, which is why the risk concentrates around pregnancy-related evacuation.
wound healing GO:0042060 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased wound healing (GO:0042060). GO:0042060 is a biological process from the Gene Ontology. ↑ INCREASED
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
Post-Injury Inflammatory Response Tissue injury elicits the inflammatory phase of the wound-healing response.
Endometrial Epithelial Loss and Differentiation Signalling Failure Destruction of the regenerative basal compartment removes the source from which the epithelium is normally rebuilt.
Show evidence (2 references)
PMID:30936754 SUPPORT 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.
PMID:21437822 SUPPORT Human Clinical
"Although it usually occurs following curettage of the pregnant or recently pregnant uterus, any uterine surgery can lead to intrauterine adhesions (IUA)."
Supports the pregnancy-associated concentration of risk while keeping the node general to uterine surgery.
Post-Injury Inflammatory Response
Inflammation is the first phase of repair and, in Asherman syndrome, persists as a feature of the diseased niche rather than resolving. Single-cell profiling of Asherman endometrium describes a niche whose cell-to-cell communication and expression profiles are simultaneously pro-fibrotic, pro-inflammatory and anti-angiogenic — the last of these matters because it works against the revascularization a regenerative repair would require.
macrophage CL:0000235 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves macrophage (CL:0000235). CL:0000235 is a cell type from the Cell Ontology.
inflammatory response GO:0006954 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased inflammatory response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology. ↑ INCREASED angiogenesis GO:0001525 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased angiogenesis (GO:0001525). GO:0001525 is a biological process from the Gene Ontology. ↓ DECREASED
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
Myofibroblast Generation and Mesenchymal Activation Inflammatory signalling drives the mesenchymal activation step of the fibrotic programme.
Show evidence (2 references)
PMID:37735465 SUPPORT 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."
Human single-cell evidence for a persistently inflammatory and anti-angiogenic niche, which is what this node asserts.
PMID:39613882 SUPPORT Human Clinical
"we briefly described the advances in the pathogenesis of IUA, with focus on inflammation and parenchymal cellular homeostasis disruption, defects in autophagy and the role of ferroptosis"
Places inflammation first among the mechanisms this review identifies as central to IUA pathogenesis.
Endometrial Epithelial Loss and Differentiation Signalling Failure
The endometrium-specific arm, and the reason this disease is not simply fibrosis in a uterus. Single-cell analysis of over 200,000 cells from Asherman patients found loss of the endometrial epithelium together with alterations in the Wnt and Notch pathways that direct epithelial differentiation, and the appearance during the implantation window of a characteristic epithelium expressing secretory leukocyte protease inhibitor. Losing the epithelium is not merely a consequence of scarring — it removes the compartment whose regeneration would otherwise close the wound without scar, so this node is both a consequence of the injury and a driver of the fibrotic outcome.
Defective epithelial autophagy (DIO2-MAPK/ERK-MTOR) drives epithelial-mesenchymal transition Increased ferroptosis load in injured endometrium amplifies epithelial EMT and fibrosis
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.
Wnt signaling pathway GO:0016055 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. ↕ DYSREGULATED Notch signaling pathway GO:0007219 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. ↕ DYSREGULATED
endometrium epithelium UBERON:0004811 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in endometrium epithelium (UBERON:0004811). UBERON:0004811 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Myofibroblast Generation and Mesenchymal Activation Epithelial cells that undergo epithelial-mesenchymal transition, rather than being replaced, contribute directly to the myofibroblast pool. Both the autophagy-defect and ferroptosis hypotheses act on this edge, and both were demonstrated on the epithelial compartment specifically. Defective epithelial autophagy (DIO2-MAPK/ERK-MTOR) drives epithelial-mesenchymal transition Increased ferroptosis load in injured endometrium amplifies epithelial EMT and fibrosis
Non-Regenerative Fibrotic Repair and Excessive ECM Deposition Failure to rebuild epithelium leaves the wound to be closed by connective tissue.
Loss of Receptive Endometrium and Implantation Failure The window-of-implantation epithelium is itself abnormal, independently of the mechanical effect of adhesions.
Show evidence (1 reference)
PMID:37735465 SUPPORT 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."
The direct human observation of epithelial loss and of the Wnt/Notch differentiation-signalling alterations this node asserts.
Defective Epithelial Autophagy
An amplifier arm, not part of the asserted canonical chain. Autophagy is defective in the endometrium of Asherman patients in association with DIO2 downregulation; in endometrial epithelial cells, inhibiting autophagy with chloroquine promotes epithelial-mesenchymal transition while rapamycin attenuates it, and silencing DIO2 blocks autophagic flux and drives EMT via MAPK/ERK-MTOR. Rapamycin and triiodothyronine both blunted endometrial fibrosis in an IUA-like mouse model.
Defective epithelial autophagy (DIO2-MAPK/ERK-MTOR) drives epithelial-mesenchymal transition
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 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. ↓ DECREASED
Downstream
Endometrial Epithelial Loss and Differentiation Signalling Failure Loss of autophagic flux destabilizes epithelial homeostasis and pushes epithelial cells toward a mesenchymal phenotype. Defective epithelial autophagy (DIO2-MAPK/ERK-MTOR) drives epithelial-mesenchymal transition
Show evidence (2 references)
PMID:35196191 SUPPORT 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."
Bidirectional pharmacological manipulation in endometrial epithelial cells — the strongest causal evidence available for this arm.
PMID:35196191 SUPPORT 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"
In vivo corroboration in mouse, kept separate from the in vitro item so the evidence tiers are not blended.
Endometrial Ferroptosis
A second amplifier arm. RNA-seq of endometrium from four patients with severe intrauterine adhesions against four normal controls showed an increased ferroptosis load, localized by immunohistochemistry; erastin-induced ferroptosis promoted EMT and fibrosis in endometrial epithelial cells, and ferrostatin-1 significantly ameliorated fibrosis in a dual-injury murine model. The stimulus did not act on stromal cells directly, so the arm is wired through the epithelium.
Increased ferroptosis load in injured endometrium amplifies epithelial EMT and fibrosis
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.
ferroptosis GO:0097707 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased ferroptosis (GO:0097707). GO:0097707 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Endometrial Epithelial Loss and Differentiation Signalling Failure Ferroptotic death and stress in the epithelial compartment promote epithelial-mesenchymal transition and epithelial loss. Increased ferroptosis load in injured endometrium amplifies epithelial EMT and fibrosis
Show evidence (2 references)
PMID:37302615 SUPPORT Human Clinical
"we performed an RNA-seq of the endometria from 4 severe IUA patients and 4 normal controls"
Establishes that the ferroptosis signal was first observed in human Asherman endometrium, not only in models. The cohort is four patients, which is why the arm stays EMERGING.
PMID:37302615 SUPPORT Model Organism
"the ferroptosis inhibitor Fer-1 significantly ameliorated endometrial fibrosis in a dual-injury IUA murine model"
Rescue experiment supporting a causal rather than bystander role, in mouse.
Myofibroblast Generation and Mesenchymal Activation
The effector cell of the fibrotic programme. Myofibroblasts in endometrial fibrosis arise from more than one source: epithelial-mesenchymal transition of endometrial epithelial cells is the best-supported route in human tissue, and endothelial-to-mesenchymal transition has been demonstrated in a rat model, where CD31/alpha-SMA double-positive cells appear in the endometrium with falling CD31 and rising alpha-SMA and vimentin. This is the conserved mesenchymal-activation step of the fibrotic response module, with the organ-specific substitution being that the activated cell derives from epithelium and endothelium rather than from a resident tissue fibroblast population.
myofibroblast cell CL:0000186 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves myofibroblast cell (CL:0000186). CL:0000186 is a cell type from the Cell Ontology. 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. 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.
epithelial to mesenchymal transition GO:0001837 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. ↑ INCREASED fibroblast activation GO:0072537 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased fibroblast activation (GO:0072537). GO:0072537 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Non-Regenerative Fibrotic Repair and Excessive ECM Deposition Activated myofibroblasts deposit the collagen-rich matrix that constitutes the scar.
Show evidence (2 references)
PMID:37302615 SUPPORT In Vitro
"We previously demonstrated that epithelial-mesenchymal transition (EMT) and fibrosis of endometrial stromal cells (HESCs) played a vital role in the development of IUA"
States EMT and stromal-cell fibrosis as the established effector mechanism of intrauterine adhesion formation.
PMID:34996477 SUPPORT Model Organism
"Endothelial cells promote the emergence of fibroblasts via the EndMT during the endometrial fibrosis of intrauterine adhesions."
Supports the endothelial contribution to the myofibroblast pool, in a rat model.
Non-Regenerative Fibrotic Repair and Excessive ECM Deposition
The switch point of the disease. Endometrium normally rebuilds after shedding without scarring — it is one of the few adult mammalian tissues that does so routinely, including after the substantial tissue loss of parturition. After certain assaults, that programme fails and fibrous connective tissue is laid down in place of endometrium. It is the substitution rather than the quantity of matrix that defines the disease: the cavity is lined by scar where it should be lined by regenerating mucosa.
extracellular matrix organization GO:0030198 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased extracellular matrix organization (GO:0030198). GO:0030198 is a biological process from the Gene Ontology. ↑ INCREASED collagen fibril organization GO:0030199 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased collagen fibril organization (GO:0030199). GO:0030199 is a biological process from the Gene Ontology. ↑ INCREASED
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
Intrauterine Adhesion Formation and Cavity Obliteration Scar tissue on opposing endometrial surfaces of a collapsed cavity adheres, converting mural fibrosis into bridging adhesions.
Show evidence (3 references)
PMID:39613882 SUPPORT 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.
PMID:37843929 SUPPORT Human Clinical
"following some assaults, including medical procedures and infections, the endometrium fails to regenerate and instead forms scars that may interfere with normal endometrial function and contribute to infertility"
Frames the disease as a failure of an ordinarily scarless regenerative programme, which is the framing this node depends on.
PMID:37843929 SUPPORT Human Clinical
"Substantial portions of the endometrium are shed during childbirth (parturition) and, in some species, menstruation, but the tissue is rapidly rebuilt without scarring"
Establishes the scarless baseline against which Asherman syndrome is a deviation.
Intrauterine Adhesion Formation and Cavity Obliteration
The defining pathological structure. Because the uterine cavity is a potential space whose walls lie in apposition, fibrotic repair of opposing denuded surfaces produces bands of scar that bridge them. The result is partial or complete obliteration of the uterine cavity and, when the injury extends to the lower segment, of the cervical canal. Severity grading in the hysteroscopic classification systems tracks the extent and location of these bridges, and severity predicts reproductive prognosis.
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
Loss of Receptive Endometrium and Implantation Failure Obliteration of the cavity removes the surface available for implantation and placentation.
Menstrual Outflow Obstruction Adhesions in the cavity and cervical canal obstruct the egress of menstrual effluent.
Show evidence (2 references)
PMID:39613882 SUPPORT 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.
PMID:30936754 SUPPORT Human Clinical
"Intrauterine adherences are classified in accordance with different classification systems based on the hysteroscopic diagnosis of severity and localization of adherences."
Supports the severity/localization grading referenced in the description.
Loss of Receptive Endometrium and Implantation Failure
Two mechanisms converge here and the entry keeps both: the mechanical loss of implantation surface from cavity obliteration, and the intrinsic abnormality of the residual epithelium during the window of implantation seen at single-cell resolution. This is the node that produces the infertility and recurrent-pregnancy-loss phenotypes, and it is also why restoring cavity patency surgically does not restore fertility to baseline.
embryo implantation GO:0007566 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased embryo implantation (GO:0007566). GO:0007566 is a biological process from the Gene Ontology. ↓ DECREASED
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.
Show evidence (2 references)
PMID:37735465 SUPPORT Human Clinical
"Asherman's Syndrome is characterized by intrauterine adhesions or scarring, which cause infertility, menstrual abnormalities, and recurrent pregnancy loss."
Attributes infertility and recurrent pregnancy loss to the adhesive/scarring lesion.
PMID:30713131 SUPPORT Human Clinical
"The pregnancy rate in women with severe adhesion was significantly lower than that in women with mild adhesion (P = 0.021)."
Supports a dose-response between adhesion burden and reproductive failure. PARTIAL because it is measured after adhesiolysis, so it bounds the residual deficit rather than the untreated state.
Menstrual Outflow Obstruction
Where adhesions obstruct the cavity or cervical canal, menstrual effluent cannot escape. Most affected women have hypomenorrhea or amenorrhea, but up to a quarter menstruate painlessly and normally, so preserved menses does not exclude the diagnosis. In amenorrhoeic women the trapped effluent produces cyclic pelvic pain, and the accompanying retrograde menstruation is a recognized route to endometriosis — a second disease generated by the first.
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.
Show evidence (1 reference)
PMID:21437822 SUPPORT 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.
⬡

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

7
Genitourinary 2
Amenorrhea FREQUENT 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 Human Clinical
"Most women with IUA have amenorrhea or hypomenorrhea"
Places amenorrhea within the majority menstrual presentation. The snippet does not separate the two, so the band is inherited from the pair rather than measured for amenorrhea alone.
Female infertility FREQUENT 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 Human Clinical
"IUA is a common cause of the refractory uterine infertility."
Names intrauterine adhesions as a common cause of refractory uterine-factor infertility.
PMID:21437822 SUPPORT Human Clinical
"In addition to abnormal menses, infertility and recurrent spontaneous abortion are common complaints."
Second, independent source describing infertility as a common presenting complaint, supporting the FREQUENT band.
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 Human Clinical
"Those who have amenorrhea may also have cyclic pelvic pain caused by outflow obstruction."
States both the phenotype and its mechanism, and restricts it to the amenorrhoeic subgroup, which is why no frequency band is asserted.
Other 4
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 Human Clinical
"Asherman's Syndrome is characterized by intrauterine adhesions or scarring, which cause infertility, menstrual abnormalities, and recurrent pregnancy loss."
Adhesions are the definitional feature of the syndrome, which is what OBLIGATE asserts here.
Hypomenorrhea FREQUENT 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.
Show evidence (1 reference)
PMID:21437822 SUPPORT Human Clinical
"Most women with IUA have amenorrhea or hypomenorrhea, but up to a fourth have painless menses of normal flow and duration."
"Most women" with amenorrhea or hypomenorrhea supports a FREQUENT band for the reduced-flow presentation, and the same sentence bounds it by naming the quarter with normal menses.
Recurrent pregnancy loss
Show evidence (1 reference)
PMID:21437822 SUPPORT Human Clinical
"In addition to abnormal menses, infertility and recurrent spontaneous abortion are common complaints."
Supports recurrent spontaneous abortion as a recognized presentation. No `frequency:` band is asserted: this snippet supports the association only, and the one number available (a 17.7% pooled early pregnancy loss rate *after* adhesiolysis) measures a post-treatment outcome, not how often recurrent loss is a presenting feature of untreated disease.
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 Human Clinical
"The accompanying retrograde menstruation may lead to endometriosis."
The source states this as a possible consequence ("may lead to"), so no frequency is asserted and the phenotype is recorded as a sequela rather than a core feature.
💊

Medical Actions

5
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. Ontology label: Hysteroscopy NCIT:C148437
Division of intrauterine adhesions under hysteroscopic vision, working from the centre of the cavity toward the periphery, is the definitive treatment and the gold standard of care. Miniature scissors are favoured over energy devices, on the reasoning that cold division avoids adding thermal injury to a tissue whose disease is caused by injury in the first place.
Mechanism Target:
INHIBITS Intrauterine Adhesion Formation and Cavity Obliteration — Mechanically divides the fibrous bridges, restoring the cavity. It removes the structure, not the tendency to form it, which is why adjuncts to prevent reformation are needed.
Show evidence (2 references)
PMID:28582327 SUPPORT Human Clinical
"Surgical management with hysteroscopic lysis of adhesions is the gold standard for treatment and adopting an office-based approach offers several advantages."
Establishes hysteroscopic adhesiolysis as the standard of care.
PMID:21437822 SUPPORT Human Clinical
"The most efficacious appears to be the use of miniature scissors for adhesiolysis and the placement of a balloon stent inside the uterus immediately after surgery."
Supports the choice of cold scissors over energy devices described here, and pairs it with the balloon stent curated as a separate treatment.
Postoperative estrogen therapy
Action: estrogen therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is estrogen therapy (NCIT:C15483). NCIT:C15483 is a clinical intervention from the NCI Thesaurus. Ontology label: Estrogen Therapy NCIT:C15483
Agent: estradiol CHEBI:16469 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses estradiol, annotated with 17beta-estradiol (CHEBI:16469). CHEBI:16469 is a therapeutic agent from Chemical Entities of Biological Interest.
Estrogen is given after adhesiolysis to stimulate regrowth of endometrium over the denuded cavity. It is the one treatment in the standard regimen that acts on the regenerative failure rather than on the scar, and it is conditional on residual basalis surviving somewhere in the cavity. Its clinical benefit is contested. A randomised trial withholding estrogen after successful adhesiolysis found no reduction in adhesion recurrence and no better reproductive outcome, so the entry curates the practice and its stated mechanism alongside the trial that fails to confirm any advantage from it.
Mechanism Target:
INHIBITS Endometrial Epithelial Loss and Differentiation Signalling Failure — Pharmacological estrogen drives proliferation of any surviving endometrium across the raw surface, opposing the epithelial-loss arm of the disease.
Show evidence (2 references)
PMID:21437822 SUPPORT Human Clinical
"Postoperative estrogen therapy is prescribed to stimulate endometrial regrowth."
States both the intervention and the mechanism claimed for it.
PMID:37396823 REFUTE Human Clinical
"Women who did not receive estrogen did not have more recurrences of adhesions in the first year prior to pregnancy (66.1% in the usual care group, 52.7% in the no-estrogen group, p = 0.15)."
A single-blind randomised trial of 114 women contradicts the clinical benefit claimed for the standard regimen: withholding estrogen after successful adhesiolysis did not increase adhesion recurrence, and pregnancy and live-birth rates at 3 years likewise did not differ. REFUTE is scoped to the outcome claim; the trial does not test whether estrogen drives proliferation of residual endometrium, so the mechanism curated in `target_mechanisms` is limited by this result rather than overturned by it.
Intrauterine barrier device after adhesiolysis
Action: intrauterine barrier placement after adhesiolysisNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is intrauterine barrier placement after adhesiolysis, annotated with Therapeutic Procedure (NCIT:C49236). NCIT:C49236 is a clinical intervention from the NCI Thesaurus. Ontology label: Therapeutic Procedure NCIT:C49236
A balloon catheter or intrauterine contraceptive device placed after adhesiolysis holds the walls of the cavity apart during healing. The mechanistic logic is specific to this disease: adhesions form because opposing denuded surfaces heal in contact, so keeping them separated during the vulnerable window addresses the geometry rather than the fibrosis. No single method has shown superiority for preventing recurrence, which the entry records rather than smoothing over.
Mechanism Target:
INHIBITS Intrauterine Adhesion Formation and Cavity Obliteration — Physically separates the opposing raw surfaces so that fibrotic repair cannot bridge them.
Show evidence (2 references)
PMID:30936754 SUPPORT Human Clinical
"Use of intrauterine devices like balloon catheters or intrauterine contraceptive devices seems to be the preferred methods for the prevention of re-occurrence of adhesions after treatment."
Supports barrier placement as the preferred adjunct, with the hedged wording ("seems to be") preserved.
PMID:28582327 SUPPORT Human Clinical
"Prevention of reformation of adhesions remains challenging and no single method for preventing recurrence has shown superiority."
Retained as an explicit limit: the barrier approach is preferred by practice rather than by demonstrated superiority.
Endometrial stem/progenitor cell therapy
Action: stem cell therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is stem cell therapy (NCIT:C165194). NCIT:C165194 is a clinical intervention from the NCI Thesaurus. Ontology label: Stem Cell Therapy NCIT:C165194
Investigational. Cell-based approaches aim to repopulate the regenerative compartment the disease destroys — the only strategy on this list that addresses the primary lesion rather than its consequences. It is curated here because it is the mechanistically matched intervention, not because it is established therapy; the evidence base remains preclinical and early clinical.
Mechanism Target:
INHIBITS Endometrial Epithelial Loss and Differentiation Signalling Failure — Restores a regenerative cell population capable of rebuilding endometrium, opposing the epithelial-loss arm.
Show evidence (2 references)
PMID:28582327 SUPPORT Human Clinical
"Cell-based therapies using endometrial stem/progenitor cells hold promise for future use in regenerating inadequate endometrium."
Records the approach at the strength the source claims for it — promise for future use, not present efficacy — hence PARTIAL.
PMID:30760192 SUPPORT Human Clinical
"Numerous studies have begun exploring the molecular mechanisms behind the fibrotic process underlying Asherman's Syndrome as well as the role of stem cells in the regeneration of the endometrium as a treatment modality."
Records the existence and stage of the stem-cell approach as a treatment modality under investigation; the same review highlights current gaps in research, so nothing stronger is claimed.
Antituberculous therapy for genital tuberculosis
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: antitubercular agent NCIT:C280 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses antitubercular agent (NCIT:C280). NCIT:C280 is a therapeutic agent from the NCI Thesaurus.
Where genital tuberculosis is the cause, antituberculous chemotherapy is the disease-directed treatment. It is included because it is the one etiology on this entry with an active, treatable upstream driver rather than a completed historical injury — and, unusually, menstrual function may partially return with treatment alone.
Mechanism Target:
INHIBITS Endometrial Basal Layer Injury — Eradicating the mycobacterial infection removes the ongoing source of endometrial injury.
Show evidence (1 reference)
PMID:31388435 SUPPORT Human Clinical
"The patient was treated with 9 months of antituberculous therapy. While she has not yet succeeded in becoming pregnant, the patient has started to notice cyclic spotting, indicating possible return of menses."
A single case with a partial menstrual response and no pregnancy — PARTIAL is the honest classification, and the snippet preserves the negative fertility outcome alongside the positive menstrual one.
🔬

Diagnosis

1
Hysteroscopy
Hysteroscopy is the gold standard for diagnosis and simultaneously the route to treatment; it also provides the severity and localization grading on which prognosis and surgical planning depend. Less invasive contrast sonohysterography or hysterosalpingography is used for initial evaluation, and MRI is required when the cavity is totally obliterated.
hysteroscopy NCIT:C148437 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:39613882 SUPPORT Human Clinical
"Hysteroscopy is the gold standard for diagnosis of IUA."
Establishes hysteroscopy as the diagnostic standard.
PMID:30936754 SUPPORT Human Clinical
"For initial diagnosis the less invasive contrast sonohysterography or hysterosalpingography is useful. The final diagnosis is based on hysteroscopy. Magnetic resonance imaging is required in cases with totally obliterated uterine cavity."
Supports the staged imaging pathway described here.
📈

Progression

1
Reproductive outcome after hysteroscopic adhesiolysis
Pooled across 54 studies and 4,640 women, roughly half conceive after adhesiolysis, but the pregnancies that follow are high-risk in a way that is mechanistically continuous with the disease: placenta accreta syndrome in about one in ten (10.1%) reflects implantation onto a scarred, basalis-deficient decidua, the same lesion that caused the infertility. The losses are also distributed across gestation rather than concentrated early — early pregnancy loss 17.7% and mid-trimester loss 11.5% — with cervical incompetence reported at 12.5% in the two studies that measured it. Ectopic pregnancy at 4.2% is the smallest of these. Antenatal surveillance for abnormal placentation is therefore part of the disease course, not an incidental precaution.
Show evidence (3 references)
PMID:30713131 SUPPORT Human Clinical
"The pooled rate of pregnancy was 50.7%"
The pooled conception rate after adhesiolysis across 53 studies. Quoted as a short fragment because the confidence interval that follows it in the source is parenthesised as "(95% CI [confidence interval]: 49.1 to 52.3)", and the bracketed gloss is stripped from snippets before matching, so the longer quote cannot be verified verbatim.
PMID:30713131 SUPPORT 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..."
The five adverse-outcome rates quoted in this record, including the placenta accreta figure that motivates the antenatal-surveillance point.
PMID:21437822 SUPPORT Human Clinical
"Follow-up studies to assure resolution of the scarring are mandatory before the patient attempts to conceive as is careful monitoring of pregnancies for cervical incompetence, placenta accreta, and intrauterine growth retardation."
Supports the surveillance recommendation and names the same three pregnancy complications.
📊

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
Pooled prevalence of intrauterine adhesions detected at hysteroscopy in 912 women from 10 prospective studies, 19.1% (95% CI 12.8-27.5%). This is the prevalence of the lesion after a defined insult, not the population prevalence of symptomatic Asherman syndrome; the same review notes that more than half the adhesions found were mild and of unknown clinical relevance.
Show evidence (2 references)
PMID:24082042 SUPPORT 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 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

2
Number of curettage procedures as the principal risk gradient
Risk of intrauterine adhesions rises with the number of miscarriages, and the meta-analysis identifies the number of dilatation and curettage procedures as the driver behind that association rather than the miscarriages themselves. This is the actionable epidemiology of the disease: it argues for minimizing instrumental evacuation, and it is the basis of the case for medical or expectant management of early pregnancy loss where feasible.
Show evidence (1 reference)
PMID:24082042 SUPPORT Human Clinical
"Relative to women with one miscarriage, women with two or three or more miscarriages showed an increased risk of IUAs by a pooled OR of 1.41 and 2.1, respectively. The number of dilatation and curettage (D&C) procedures seemed to be the main driver behind these associations."
Quantifies the dose-response and attributes it to the D&C count rather than to miscarriage per se.
Genital tuberculosis as an etiology in endemic settings
In tuberculosis-endemic regions genital tuberculosis is a non-iatrogenic route to Asherman syndrome and to uterine-factor infertility. It matters clinically because the treatment differs — the adhesions are the end product of an active infection, and antituberculous therapy is the disease-directed intervention.
Show evidence (2 references)
PMID:31388435 SUPPORT Human Clinical
"We present a case of genital tuberculosis causing Asherman's syndrome and resultant infertility."
A single case report, which is the level of evidence this entry claims for the tuberculous etiology.
PMID:31388435 SUPPORT Human Clinical
"it is a leading cause of infertility in endemic countries. The global incidence of tuberculosis (TB) is growing at approximately 0.4% per year"
Supports the endemic-setting framing at the level of tuberculous infertility generally, not of Asherman syndrome specifically — hence PARTIAL.
🔀

Differential Diagnoses

3

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

Adenomyosis
Overlapping Features Also presents with abnormal menstruation, pelvic pain and impaired fertility, but the lesion is endometrial tissue within the myometrium rather than scar within the cavity, and the cavity itself is patent at hysteroscopy.
Distinguishing Features
  • Uterine cavity patent at hysteroscopy, with no bridging fibrous bands
  • Junctional-zone thickening on MRI rather than cavity obliteration
Endometriosis
Overlapping Features Shares cyclic pelvic pain and infertility. The direction of the relationship matters here: Asherman syndrome can cause endometriosis through obstructed retrograde menstruation, so the two may coexist as sequela rather than as alternatives.
Distinguishing Features
  • Ectopic endometrial implants outside the uterus rather than intracavitary scar
Hypothalamic or ovarian causes of secondary amenorrhea
Overlapping Features Amenorrhea from an outflow-tract lesion is distinguished from endocrine amenorrhea by a normal hormonal profile with absent withdrawal bleeding, and definitively by hysteroscopy.
Distinguishing Features
  • Absent withdrawal bleeding despite adequate estrogen-progestin challenge
  • Normal gonadotropin and estradiol profile
{ }

Source YAML

click to show 
name: Asherman_Syndrome
creation_date: '2026-08-22T06:00:00Z'
category: Acquired
synonyms:
- intrauterine adhesions
- intrauterine synechiae
- uterine synechiae
- Asherman's syndrome
- IUA
description: >-
  Asherman syndrome is an acquired fibrotic disease of the uterine cavity in
  which the basal (regenerative) layer of the endometrium is destroyed, most
  often by curettage of the pregnant or recently pregnant uterus, and the
  endometrium heals by scarring instead of regenerating. The scar tissue bridges
  the opposing walls of the cavity as intrauterine adhesions, partially or
  completely obliterating the cavity and the cervical canal. Clinically it
  presents with hypomenorrhea or amenorrhea, cyclic pelvic pain from outflow
  obstruction, infertility, and recurrent pregnancy loss.

  What makes the disease mechanistically interesting is that it is a
  regeneration failure in a tissue that is otherwise an exemplar of scarless
  repair: the endometrium is shed and rebuilt without scarring dozens of times
  across the reproductive lifespan, and after parturition sheds a substantial
  portion of the tissue, yet after certain iatrogenic insults the same tissue
  scars. The entry therefore models the disease as a switch between two repair
  programmes rather than as fibrosis added on top of normal healing, and it
  conforms to the `fibrotic_response` module along the conserved
  injury-inflammation-myofibroblast-ECM chain while keeping the
  endometrium-specific epithelial-loss arm — described at single-cell resolution
  in human Asherman endometrium — as its own node.

  Three amplifier mechanisms (defective autophagy, ferroptosis, and
  endothelial-to-mesenchymal transition) are curated as EMERGING hypotheses
  rather than asserted on the canonical chain, because each rests on patient
  tissue plus rodent or in vitro perturbation rather than on human
  interventional evidence.
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
mechanistic_hypotheses:
- hypothesis_group_id: nonregenerative_fibrotic_repair
  hypothesis_label: Basalis destruction switches endometrial repair from regeneration to scarring
  status: CANONICAL
  description: >-
    The accepted account. Injury that removes or destroys the endometrial basal
    layer eliminates the regenerative compartment from which the functionalis is
    normally rebuilt. Repair then proceeds by the generic fibrotic route —
    inflammation, myofibroblast generation, collagen deposition — and the
    resulting fibrous connective tissue replaces endometrium rather than being
    remodelled away. Because the injury is typically to opposing surfaces of a
    collapsed cavity, the scar bridges them, producing adhesions rather than
    simple mural fibrosis.
  evidence:
  - reference: PMID:39613882
    reference_title: Mechanistic insights into intrauterine adhesions.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Intrauterine adhesions (IUA), also known as Asherman's syndrome, arise
      from damage to the basal layer of the endometrium, frequently caused by
      intrauterine interventions. This damage leads to nonregenerative healing
      of endometrium resulting in replacement by fibrous connective tissue
    explanation: >-
      States the canonical chain in one sentence: basalis damage, then
      nonregenerative healing, then fibrous replacement.
- hypothesis_group_id: autophagy_defect_emt
  hypothesis_label: Defective epithelial autophagy (DIO2-MAPK/ERK-MTOR) drives epithelial-mesenchymal transition
  status: EMERGING
  description: >-
    Autophagy is defective in the endometrium of Asherman patients and is
    associated with DIO2 downregulation. In endometrial epithelial cells,
    blocking autophagy pharmacologically promotes EMT and enhancing it with
    rapamycin attenuates EMT; silencing DIO2 blocks autophagic flux and drives
    EMT through MAPK/ERK-MTOR. The patient observation is correlative and every
    causal step is cell-culture or mouse, so this is curated as an amplifier
    hypothesis rather than as part of the canonical chain.
  evidence:
  - reference: PMID:35196191
    reference_title: Defective autophagy contributes to endometrial epithelial-mesenchymal transition in intrauterine adhesions.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we demonstrated that autophagy is defective in endometria of IUA patients,
      which aggravates EMT and endometrial fibrosis, and defective autophagy is
      related to DIO2 (iodothyronine deiodinase 2) downregulation
    explanation: >-
      States the hypothesis and names the DIO2 link. Classified IN_VITRO because
      the causal demonstrations in this paper are in endometrial epithelial cell
      culture; the patient data are descriptive.
- hypothesis_group_id: ferroptosis_amplification
  hypothesis_label: Increased ferroptosis load in injured endometrium amplifies epithelial EMT and fibrosis
  status: EMERGING
  description: >-
    RNA-seq of severe Asherman endometrium against normal controls found an
    increased ferroptosis load, and erastin-induced ferroptosis promoted EMT and
    fibrosis in endometrial epithelial cells while the ferroptosis inhibitor
    ferrostatin-1 ameliorated fibrosis in a dual-injury murine model. The
    compartment specificity matters and is preserved here: erastin did not
    produce pro-fibrotic differentiation in endometrial stromal cells directly,
    so the proposed route runs through the epithelium.
  evidence:
  - reference: PMID:37302615
    reference_title: Ferroptosis contributes to endometrial fibrosis in intrauterine adhesions.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we demonstrated that ferroptosis load is increased in IUA endometria. In
      vitro experiments showed that erastin-induced ferroptosis promoted EMT and
      fibrosis in endometrial epithelial cells
    explanation: >-
      Establishes the patient-tissue observation and the in vitro causal step
      this hypothesis rests on.
  - reference: PMID:37302615
    reference_title: Ferroptosis contributes to endometrial fibrosis in intrauterine adhesions.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      but did not lead to pro-fibrotic differentiation in endometrial stromal
      cells (HESCs)
    explanation: >-
      Retained as a deliberate negative limit on the hypothesis: the ferroptotic
      stimulus does not act directly on the stromal compartment, which is why
      the hypothesis is wired through the epithelial node and not the
      myofibroblast node.
- hypothesis_group_id: endmt_myofibroblast_origin
  hypothesis_label: Endothelial-to-mesenchymal transition contributes myofibroblasts to endometrial fibrosis
  status: EMERGING
  description: >-
    A rat intrauterine adhesion model showed cells doubly positive for the
    endothelial marker CD31 and the myofibroblast marker alpha-SMA in the
    endometrium 14 days after injury, with falling CD31 and rising alpha-SMA and
    vimentin, implicating endothelium as one source of the myofibroblast pool.
    No human confirmation was found in this curation pass, so the arm is
    EMERGING and carries a HUMAN_MODEL_MISMATCH discussion.
  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
    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: >-
      The dual-marker observation on which the EndMT origin claim rests, in a
      rat model.
pathophysiology:
- name: Endometrial Basal Layer Injury
  biological_scale: TISSUE
  description: >-
    The initiating lesion. Instrumentation of the pregnant or recently pregnant
    uterus — classically sharp curettage after miscarriage or postpartum —
    strips or destroys the basal layer of the endometrium, the compartment that
    regenerates the functionalis after each shedding. Hysteroscopic surgery,
    uterine artery embolization and uterine tuberculosis produce the same lesion
    by different routes. The gravid or recently gravid state is the important
    modifier: the same instrument used on a non-pregnant uterus is far less
    likely to cause adhesions, which is why the risk concentrates around
    pregnancy-related evacuation.
  conforms_to: fibrotic_response#Tissue Injury
  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
  biological_processes:
  - preferred_term: wound healing
    term:
      id: GO:0042060
      label: wound healing
    modifier: INCREASED
  evidence:
  - reference: PMID:30936754
    reference_title: "Asherman's syndrome: current perspectives on diagnosis and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    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.
  - reference: PMID:21437822
    reference_title: "Asherman's syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although it usually occurs following curettage of the pregnant or recently
      pregnant uterus, any uterine surgery can lead to intrauterine adhesions
      (IUA).
    explanation: >-
      Supports the pregnancy-associated concentration of risk while keeping the
      node general to uterine surgery.
  downstream:
  - target: Post-Injury Inflammatory Response
    causal_link_type: DIRECT
    description: >-
      Tissue injury elicits the inflammatory phase of the wound-healing
      response.
  - target: Endometrial Epithelial Loss and Differentiation Signalling Failure
    causal_link_type: DIRECT
    description: >-
      Destruction of the regenerative basal compartment removes the source from
      which the epithelium is normally rebuilt.
- name: Post-Injury Inflammatory Response
  biological_scale: TISSUE
  description: >-
    Inflammation is the first phase of repair and, in Asherman syndrome,
    persists as a feature of the diseased niche rather than resolving.
    Single-cell profiling of Asherman endometrium describes a niche whose
    cell-to-cell communication and expression profiles are simultaneously
    pro-fibrotic, pro-inflammatory and anti-angiogenic — the last of these
    matters because it works against the revascularization a regenerative repair
    would require.
  conforms_to: fibrotic_response#Inflammatory Recruitment and Amplification
  locations:
  - preferred_term: endometrium
    term:
      id: UBERON:0001295
      label: endometrium
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  - preferred_term: angiogenesis
    term:
      id: GO:0001525
      label: angiogenesis
    modifier: DECREASED
  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: >-
      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: >-
      Human single-cell evidence for a persistently inflammatory and
      anti-angiogenic niche, which is what this node asserts.
  - reference: PMID:39613882
    reference_title: Mechanistic insights into intrauterine adhesions.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we briefly described the advances in the pathogenesis of IUA, with focus
      on inflammation and parenchymal cellular homeostasis disruption, defects
      in autophagy and the role of ferroptosis
    explanation: >-
      Places inflammation first among the mechanisms this review identifies as
      central to IUA pathogenesis.
  downstream:
  - target: Myofibroblast Generation and Mesenchymal Activation
    causal_link_type: DIRECT
    description: >-
      Inflammatory signalling drives the mesenchymal activation step of the
      fibrotic programme.
- name: Endometrial Epithelial Loss and Differentiation Signalling Failure
  biological_scale: CELLULAR
  description: >-
    The endometrium-specific arm, and the reason this disease is not simply
    fibrosis in a uterus. Single-cell analysis of over 200,000 cells from
    Asherman patients found loss of the endometrial epithelium together with
    alterations in the Wnt and Notch pathways that direct epithelial
    differentiation, and the appearance during the implantation window of a
    characteristic epithelium expressing secretory leukocyte protease inhibitor.
    Losing the epithelium is not merely a consequence of scarring — it removes
    the compartment whose regeneration would otherwise close the wound without
    scar, so this node is both a consequence of the injury and a driver of the
    fibrotic outcome.
  locations:
  - preferred_term: endometrium epithelium
    term:
      id: UBERON:0004811
      label: endometrium epithelium
  cell_types:
  - preferred_term: endometrial epithelial cell
    term:
      id: CL:0002149
      label: epithelial cell of uterus
  biological_processes:
  - preferred_term: Wnt signaling pathway
    term:
      id: GO:0016055
      label: Wnt signaling pathway
    modifier: DYSREGULATED
  - preferred_term: Notch signaling pathway
    term:
      id: GO:0007219
      label: Notch signaling pathway
    modifier: DYSREGULATED
  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: >-
      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: >-
      The direct human observation of epithelial loss and of the Wnt/Notch
      differentiation-signalling alterations this node asserts.
  downstream:
  - target: Myofibroblast Generation and Mesenchymal Activation
    causal_link_type: DIRECT
    hypothesis_groups:
    - autophagy_defect_emt
    - ferroptosis_amplification
    description: >-
      Epithelial cells that undergo epithelial-mesenchymal transition, rather
      than being replaced, contribute directly to the myofibroblast pool. Both
      the autophagy-defect and ferroptosis hypotheses act on this edge, and both
      were demonstrated on the epithelial compartment specifically.
  - target: Non-Regenerative Fibrotic Repair and Excessive ECM Deposition
    causal_link_type: DIRECT
    description: >-
      Failure to rebuild epithelium leaves the wound to be closed by connective
      tissue.
  - target: Loss of Receptive Endometrium and Implantation Failure
    causal_link_type: DIRECT
    description: >-
      The window-of-implantation epithelium is itself abnormal, independently of
      the mechanical effect of adhesions.
- name: Defective Epithelial Autophagy
  biological_scale: CELLULAR
  description: >-
    An amplifier arm, not part of the asserted canonical chain. Autophagy is
    defective in the endometrium of Asherman patients in association with DIO2
    downregulation; in endometrial epithelial cells, inhibiting autophagy with
    chloroquine promotes epithelial-mesenchymal transition while rapamycin
    attenuates it, and silencing DIO2 blocks autophagic flux and drives EMT via
    MAPK/ERK-MTOR. Rapamycin and triiodothyronine both blunted endometrial
    fibrosis in an IUA-like mouse model.
  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
  evidence:
  - reference: PMID:35196191
    reference_title: Defective autophagy contributes to endometrial epithelial-mesenchymal transition in intrauterine adhesions.
    supports: SUPPORT
    evidence_source: IN_VITRO
    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: >-
      Bidirectional pharmacological manipulation in endometrial epithelial cells
      — the strongest causal evidence available for this arm.
  - reference: PMID:35196191
    reference_title: Defective autophagy contributes to endometrial epithelial-mesenchymal transition in intrauterine adhesions.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    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: >-
      In vivo corroboration in mouse, kept separate from the in vitro item so the
      evidence tiers are not blended.
  downstream:
  - target: Endometrial Epithelial Loss and Differentiation Signalling Failure
    causal_link_type: DIRECT
    hypothesis_groups:
    - autophagy_defect_emt
    description: >-
      Loss of autophagic flux destabilizes epithelial homeostasis and pushes
      epithelial cells toward a mesenchymal phenotype.
- name: Endometrial Ferroptosis
  biological_scale: CELLULAR
  description: >-
    A second amplifier arm. RNA-seq of endometrium from four patients with
    severe intrauterine adhesions against four normal controls showed an
    increased ferroptosis load, localized by immunohistochemistry;
    erastin-induced ferroptosis promoted EMT and fibrosis in endometrial
    epithelial cells, and ferrostatin-1 significantly ameliorated fibrosis in a
    dual-injury murine model. The stimulus did not act on stromal cells
    directly, so the arm is wired through the epithelium.
  cell_types:
  - preferred_term: endometrial epithelial cell
    term:
      id: CL:0002149
      label: epithelial cell of uterus
  biological_processes:
  - preferred_term: ferroptosis
    term:
      id: GO:0097707
      label: ferroptosis
    modifier: INCREASED
  evidence:
  - reference: PMID:37302615
    reference_title: Ferroptosis contributes to endometrial fibrosis in intrauterine adhesions.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we performed an RNA-seq of the endometria from 4 severe IUA patients and 4
      normal controls
    explanation: >-
      Establishes that the ferroptosis signal was first observed in human
      Asherman endometrium, not only in models. The cohort is four patients,
      which is why the arm stays EMERGING.
  - reference: PMID:37302615
    reference_title: Ferroptosis contributes to endometrial fibrosis in intrauterine adhesions.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      the ferroptosis inhibitor Fer-1 significantly ameliorated endometrial
      fibrosis in a dual-injury IUA murine model
    explanation: >-
      Rescue experiment supporting a causal rather than bystander role, in
      mouse.
  downstream:
  - target: Endometrial Epithelial Loss and Differentiation Signalling Failure
    causal_link_type: DIRECT
    hypothesis_groups:
    - ferroptosis_amplification
    description: >-
      Ferroptotic death and stress in the epithelial compartment promote
      epithelial-mesenchymal transition and epithelial loss.
- name: Myofibroblast Generation and Mesenchymal Activation
  biological_scale: CELLULAR
  description: >-
    The effector cell of the fibrotic programme. Myofibroblasts in endometrial
    fibrosis arise from more than one source: epithelial-mesenchymal transition
    of endometrial epithelial cells is the best-supported route in human tissue,
    and endothelial-to-mesenchymal transition has been demonstrated in a rat
    model, where CD31/alpha-SMA double-positive cells appear in the endometrium
    with falling CD31 and rising alpha-SMA and vimentin. This is the conserved
    mesenchymal-activation step of the fibrotic response module, with the
    organ-specific substitution being that the activated cell derives from
    epithelium and endothelium rather than from a resident tissue fibroblast
    population.
  conforms_to: fibrotic_response#Mesenchymal Cell Activation
  cell_types:
  - preferred_term: myofibroblast cell
    term:
      id: CL:0000186
      label: myofibroblast cell
  - preferred_term: stromal cell of endometrium
    term:
      id: CL:0002255
      label: stromal cell of endometrium
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: epithelial to mesenchymal transition
    term:
      id: GO:0001837
      label: epithelial to mesenchymal transition
    modifier: INCREASED
  - preferred_term: fibroblast activation
    term:
      id: GO:0072537
      label: fibroblast activation
    modifier: INCREASED
  evidence:
  - reference: PMID:37302615
    reference_title: Ferroptosis contributes to endometrial fibrosis in intrauterine adhesions.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We previously demonstrated that epithelial-mesenchymal transition (EMT)
      and fibrosis of endometrial stromal cells (HESCs) played a vital role in
      the development of IUA
    explanation: >-
      States EMT and stromal-cell fibrosis as the established effector mechanism
      of intrauterine adhesion formation.
  - 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
    snippet: >-
      Endothelial cells promote the emergence of fibroblasts via the EndMT
      during the endometrial fibrosis of intrauterine adhesions.
    explanation: >-
      Supports the endothelial contribution to the myofibroblast pool, in a rat
      model.
  downstream:
  - target: Non-Regenerative Fibrotic Repair and Excessive ECM Deposition
    causal_link_type: DIRECT
    description: >-
      Activated myofibroblasts deposit the collagen-rich matrix that constitutes
      the scar.
- name: Non-Regenerative Fibrotic Repair and Excessive ECM Deposition
  biological_scale: TISSUE
  description: >-
    The switch point of the disease. Endometrium normally rebuilds after
    shedding without scarring — it is one of the few adult mammalian tissues
    that does so routinely, including after the substantial tissue loss of
    parturition. After certain assaults, that programme fails and fibrous
    connective tissue is laid down in place of endometrium. It is the
    substitution rather than the quantity of matrix that defines the disease:
    the cavity is lined by scar where it should be lined by regenerating mucosa.
  conforms_to: fibrotic_response#Excessive ECM Deposition
  locations:
  - preferred_term: endometrium
    term:
      id: UBERON:0001295
      label: endometrium
  biological_processes:
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: INCREASED
  - preferred_term: collagen fibril organization
    term:
      id: GO:0030199
      label: collagen fibril organization
    modifier: INCREASED
  evidence:
  - reference: PMID:39613882
    reference_title: Mechanistic insights into intrauterine adhesions.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    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.
  - reference: PMID:37843929
    reference_title: Mechanisms of Regeneration and Fibrosis in the Endometrium.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      following some assaults, including medical procedures and infections, the
      endometrium fails to regenerate and instead forms scars that may interfere
      with normal endometrial function and contribute to infertility
    explanation: >-
      Frames the disease as a failure of an ordinarily scarless regenerative
      programme, which is the framing this node depends on.
  - reference: PMID:37843929
    reference_title: Mechanisms of Regeneration and Fibrosis in the Endometrium.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Substantial portions of the endometrium are shed during childbirth
      (parturition) and, in some species, menstruation, but the tissue is
      rapidly rebuilt without scarring
    explanation: >-
      Establishes the scarless baseline against which Asherman syndrome is a
      deviation.
  downstream:
  - target: Intrauterine Adhesion Formation and Cavity Obliteration
    causal_link_type: DIRECT
    description: >-
      Scar tissue on opposing endometrial surfaces of a collapsed cavity
      adheres, converting mural fibrosis into bridging adhesions.
- name: Intrauterine Adhesion Formation and Cavity Obliteration
  biological_scale: TISSUE
  description: >-
    The defining pathological structure. Because the uterine cavity is a
    potential space whose walls lie in apposition, fibrotic repair of opposing
    denuded surfaces produces bands of scar that bridge them. The result is
    partial or complete obliteration of the uterine cavity and, when the injury
    extends to the lower segment, of the cervical canal. Severity grading in the
    hysteroscopic classification systems tracks the extent and location of these
    bridges, and severity predicts reproductive prognosis.
  conforms_to: fibrotic_response#Architectural Distortion and Organ Dysfunction
  locations:
  - preferred_term: uterus
    term:
      id: UBERON:0000995
      label: uterus
  evidence:
  - reference: PMID:39613882
    reference_title: Mechanistic insights into intrauterine adhesions.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    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.
  - reference: PMID:30936754
    reference_title: "Asherman's syndrome: current perspectives on diagnosis and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Intrauterine adherences are classified in accordance with different
      classification systems based on the hysteroscopic diagnosis of severity
      and localization of adherences.
    explanation: >-
      Supports the severity/localization grading referenced in the description.
  downstream:
  - target: Loss of Receptive Endometrium and Implantation Failure
    causal_link_type: DIRECT
    description: >-
      Obliteration of the cavity removes the surface available for implantation
      and placentation.
  - target: Menstrual Outflow Obstruction
    causal_link_type: DIRECT
    description: >-
      Adhesions in the cavity and cervical canal obstruct the egress of
      menstrual effluent.
- name: Loss of Receptive Endometrium and Implantation Failure
  biological_scale: TISSUE
  description: >-
    Two mechanisms converge here and the entry keeps both: the mechanical loss
    of implantation surface from cavity obliteration, and the intrinsic
    abnormality of the residual epithelium during the window of implantation
    seen at single-cell resolution. This is the node that produces the
    infertility and recurrent-pregnancy-loss phenotypes, and it is also why
    restoring cavity patency surgically does not restore fertility to baseline.
  locations:
  - preferred_term: endometrium
    term:
      id: UBERON:0001295
      label: endometrium
  biological_processes:
  - preferred_term: embryo implantation
    term:
      id: GO:0007566
      label: embryo implantation
    modifier: DECREASED
  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: >-
      Attributes infertility and recurrent pregnancy loss to the
      adhesive/scarring lesion.
  - reference: PMID:30713131
    reference_title: "Reproductive outcomes after surgical treatment of asherman syndrome: A systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The pregnancy rate in women with severe adhesion was significantly lower
      than that in women with mild adhesion (P = 0.021).
    explanation: >-
      Supports a dose-response between adhesion burden and reproductive failure.
      PARTIAL because it is measured after adhesiolysis, so it bounds the
      residual deficit rather than the untreated state.
- name: Menstrual Outflow Obstruction
  biological_scale: ORGANISM
  description: >-
    Where adhesions obstruct the cavity or cervical canal, menstrual effluent
    cannot escape. Most affected women have hypomenorrhea or amenorrhea, but up
    to a quarter menstruate painlessly and normally, so preserved menses does
    not exclude the diagnosis. In amenorrhoeic women the trapped effluent
    produces cyclic pelvic pain, and the accompanying retrograde menstruation is
    a recognized route to endometriosis — a second disease generated by the
    first.
  locations:
  - preferred_term: uterus
    term:
      id: UBERON:0000995
      label: uterus
  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. 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.
phenotypes:
- category: Clinical
  name: Intrauterine adhesions
  description: >-
    The defining structural finding: fibrous bands bridging the walls of the
    uterine cavity, diagnosed and graded at hysteroscopy.
  phenotype_term:
    preferred_term: Uterine synechiae
    term:
      id: HP:0030712
      label: Uterine synechiae
  frequency: OBLIGATE
  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: >-
      Adhesions are the definitional feature of the syndrome, which is what
      OBLIGATE asserts here.
- category: Clinical
  name: Hypomenorrhea
  description: >-
    Reduced menstrual flow, the commonest presenting menstrual abnormality. HPO
    has no hypomenorrhea term, so the phenotype is bound to the parent
    `Abnormality of the menstrual cycle` and the specific meaning is carried by
    `preferred_term` and this description rather than by a wrong-but-specific
    term.
  phenotype_term:
    preferred_term: Hypomenorrhea
    term:
      id: HP:0000140
      label: Abnormality of the menstrual cycle
  frequency: FREQUENT
  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: >-
      "Most women" with amenorrhea or hypomenorrhea supports a FREQUENT band for
      the reduced-flow presentation, and the same sentence bounds it by naming
      the quarter with normal menses.
- category: Clinical
  name: Amenorrhea
  description: >-
    Absence of menses, in the severe end of the spectrum where the cavity or
    cervical canal is largely obliterated.
  phenotype_term:
    preferred_term: Amenorrhea
    term:
      id: HP:0000141
      label: Amenorrhea
  frequency: FREQUENT
  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: >-
      Places amenorrhea within the majority menstrual presentation. The snippet
      does not separate the two, so the band is inherited from the pair rather
      than measured for amenorrhea alone.
- category: Clinical
  name: Female infertility
  description: >-
    Asherman syndrome is a leading cause of uterine-factor infertility, arising
    both from loss of implantation surface and from the intrinsic abnormality of
    the residual endometrium.
  phenotype_term:
    preferred_term: Female infertility
    term:
      id: HP:0008222
      label: Female infertility
  frequency: FREQUENT
  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: >-
      Names intrauterine adhesions as a common cause of refractory
      uterine-factor infertility.
  - 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: >-
      Second, independent source describing infertility as a common presenting
      complaint, supporting the FREQUENT band.
- category: Clinical
  name: Recurrent pregnancy loss
  description: >-
    Recurrent spontaneous abortion is a common presentation, reflecting failure
    of implantation and placentation on a scarred, partly obliterated cavity.

    The ontology binding is deliberately omitted. `HP:0200067` Recurrent
    spontaneous abortion is a real HPO term meaning exactly this, but it sits
    outside `HP:0000118` (phenotypic abnormality) in the pregnancy-history
    branch and so is not a member of the `PhenotypeTerm` dynamic enum.
    Substituting a term that means something else would be worse than leaving it
    unbound, so the meaning is carried by `preferred_term`. This is a further
    instance of the enum-root gap recorded as gap 3 of issue #7837, which
    `Familial_Hyperaldosteronism_Type_I` hit for `HP:0100602` and
    `Hemolytic_Disease_of_the_Fetus_and_Newborn` hit for `HP:0003826`
    Stillbirth.
  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: >-
      Supports recurrent spontaneous abortion as a recognized presentation. No
      `frequency:` band is asserted: this snippet supports the association only,
      and the one number available (a 17.7% pooled early pregnancy loss rate
      *after* adhesiolysis) measures a post-treatment outcome, not how often
      recurrent loss is a presenting feature of untreated disease.
- category: Clinical
  name: Cyclic pelvic pain
  description: >-
    Pain that recurs with the menstrual cycle in women who are amenorrhoeic,
    caused by obstruction to the egress of menstrual effluent.
  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: >-
      States both the phenotype and its mechanism, and restricts it to the
      amenorrhoeic subgroup, which is why no frequency band is asserted.
- category: Clinical
  name: Secondary endometriosis
  description: >-
    Retrograde menstruation forced by outflow obstruction is a recognized route
    from Asherman syndrome to endometriosis — a second disease produced by the
    first.
  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: >-
      The source states this as a possible consequence ("may lead to"), so no
      frequency is asserted and the phenotype is recorded as a sequela rather
      than a core feature.
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: >-
    Pooled prevalence of intrauterine adhesions detected at hysteroscopy in 912
    women from 10 prospective studies, 19.1% (95% CI 12.8-27.5%). This is the
    prevalence of the lesion after a defined insult, not the population
    prevalence of symptomatic Asherman syndrome; the same review notes that more
    than half the adhesions found were mild and of unknown clinical relevance.
  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.
  - 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.
epidemiology:
- name: Number of curettage procedures as the principal risk gradient
  description: >-
    Risk of intrauterine adhesions rises with the number of miscarriages, and
    the meta-analysis identifies the number of dilatation and curettage
    procedures as the driver behind that association rather than the
    miscarriages themselves. This is the actionable epidemiology of the disease:
    it argues for minimizing instrumental evacuation, and it is the basis of the
    case for medical or expectant management of early pregnancy loss where
    feasible.
  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: >-
      Relative to women with one miscarriage, women with two or three or more
      miscarriages showed an increased risk of IUAs by a pooled OR of 1.41 and
      2.1, respectively. The number of dilatation and curettage (D&C) procedures
      seemed to be the main driver behind these associations.
    explanation: >-
      Quantifies the dose-response and attributes it to the D&C count rather
      than to miscarriage per se.
- name: Genital tuberculosis as an etiology in endemic settings
  description: >-
    In tuberculosis-endemic regions genital tuberculosis is a non-iatrogenic
    route to Asherman syndrome and to uterine-factor infertility. It matters
    clinically because the treatment differs — the adhesions are the end product
    of an active infection, and antituberculous therapy is the disease-directed
    intervention.
  evidence:
  - reference: PMID:31388435
    reference_title: "Case report of pelvic tuberculosis resulting in Asherman's syndrome and infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We present a case of genital tuberculosis causing Asherman's syndrome and
      resultant infertility.
    explanation: >-
      A single case report, which is the level of evidence this entry claims for
      the tuberculous etiology.
  - reference: PMID:31388435
    reference_title: "Case report of pelvic tuberculosis resulting in Asherman's syndrome and infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      it is a leading cause of infertility in endemic countries. The global
      incidence of tuberculosis (TB) is growing at approximately 0.4% per year
    explanation: >-
      Supports the endemic-setting framing at the level of tuberculous
      infertility generally, not of Asherman syndrome specifically — hence
      PARTIAL.
diagnosis:
- name: Hysteroscopy
  description: >-
    Hysteroscopy is the gold standard for diagnosis and simultaneously the route
    to treatment; it also provides the severity and localization grading on
    which prognosis and surgical planning depend. Less invasive contrast
    sonohysterography or hysterosalpingography is used for initial evaluation,
    and MRI is required when the cavity is totally obliterated.
  diagnosis_term:
    preferred_term: hysteroscopy
    term:
      id: NCIT:C148437
      label: Hysteroscopy
  evidence:
  - reference: PMID:39613882
    reference_title: Mechanistic insights into intrauterine adhesions.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hysteroscopy is the gold standard for diagnosis of IUA.
    explanation: >-
      Establishes hysteroscopy as the diagnostic standard.
  - reference: PMID:30936754
    reference_title: "Asherman's syndrome: current perspectives on diagnosis and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      For initial diagnosis the less invasive contrast sonohysterography or
      hysterosalpingography is useful. The final diagnosis is based on
      hysteroscopy. Magnetic resonance imaging is required in cases with totally
      obliterated uterine cavity.
    explanation: >-
      Supports the staged imaging pathway described here.
treatments:
- name: Hysteroscopic adhesiolysis
  description: >-
    Division of intrauterine adhesions under hysteroscopic vision, working from
    the centre of the cavity toward the periphery, is the definitive treatment
    and the gold standard of care. Miniature scissors are favoured over energy
    devices, on the reasoning that cold division avoids adding thermal injury to
    a tissue whose disease is caused by injury in the first place.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: hysteroscopy
    term:
      id: NCIT:C148437
      label: Hysteroscopy
  target_mechanisms:
  - target: Intrauterine Adhesion Formation and Cavity Obliteration
    treatment_effect: INHIBITS
    description: >-
      Mechanically divides the fibrous bridges, restoring the cavity. It removes
      the structure, not the tendency to form it, which is why adjuncts to
      prevent reformation are needed.
  evidence:
  - reference: PMID:28582327
    reference_title: "A comprehensive review of Asherman's syndrome: causes, symptoms and treatment options."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Surgical management with hysteroscopic lysis of adhesions is the gold
      standard for treatment and adopting an office-based approach offers
      several advantages.
    explanation: >-
      Establishes hysteroscopic adhesiolysis as the standard of care.
  - reference: PMID:21437822
    reference_title: "Asherman's syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most efficacious appears to be the use of miniature scissors for
      adhesiolysis and the placement of a balloon stent inside the uterus
      immediately after surgery.
    explanation: >-
      Supports the choice of cold scissors over energy devices described here,
      and pairs it with the balloon stent curated as a separate treatment.
- name: Postoperative estrogen therapy
  description: >-
    Estrogen is given after adhesiolysis to stimulate regrowth of endometrium
    over the denuded cavity. It is the one treatment in the standard regimen
    that acts on the regenerative failure rather than on the scar, and it is
    conditional on residual basalis surviving somewhere in the cavity.

    Its clinical benefit is contested. A randomised trial withholding estrogen
    after successful adhesiolysis found no reduction in adhesion recurrence and
    no better reproductive outcome, so the entry curates the practice and its
    stated mechanism alongside the trial that fails to confirm any advantage
    from it.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: estrogen therapy
    term:
      id: NCIT:C15483
      label: Estrogen Therapy
    therapeutic_agent:
    - preferred_term: estradiol
      term:
        id: CHEBI:16469
        label: 17beta-estradiol
  target_mechanisms:
  - target: Endometrial Epithelial Loss and Differentiation Signalling Failure
    treatment_effect: INHIBITS
    description: >-
      Pharmacological estrogen drives proliferation of any surviving endometrium
      across the raw surface, opposing the epithelial-loss arm of the disease.
  evidence:
  - reference: PMID:21437822
    reference_title: "Asherman's syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Postoperative estrogen therapy is prescribed to stimulate endometrial
      regrowth.
    explanation: >-
      States both the intervention and the mechanism claimed for it.
  - reference: PMID:37396823
    reference_title: >-
      Hormonal support in women with Asherman syndrome does not lead to better
      outcomes: A randomized trial.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Women who did not receive estrogen did not have more recurrences of
      adhesions in the first year prior to pregnancy (66.1% in the usual care
      group, 52.7% in the no-estrogen group, p = 0.15).
    explanation: >-
      A single-blind randomised trial of 114 women contradicts the clinical
      benefit claimed for the standard regimen: withholding estrogen after
      successful adhesiolysis did not increase adhesion recurrence, and
      pregnancy and live-birth rates at 3 years likewise did not differ. REFUTE
      is scoped to the outcome claim; the trial does not test whether estrogen
      drives proliferation of residual endometrium, so the mechanism curated in
      `target_mechanisms` is limited by this result rather than overturned
      by it.
- name: Intrauterine barrier device after adhesiolysis
  description: >-
    A balloon catheter or intrauterine contraceptive device placed after
    adhesiolysis holds the walls of the cavity apart during healing. The
    mechanistic logic is specific to this disease: adhesions form because
    opposing denuded surfaces heal in contact, so keeping them separated during
    the vulnerable window addresses the geometry rather than the fibrosis. No
    single method has shown superiority for preventing recurrence, which the
    entry records rather than smoothing over.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: intrauterine barrier placement after adhesiolysis
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  notes: >-
    The generic `NCIT:C49236` binding is deliberate. NCIT has no
    clinical-intervention term for intrauterine barrier or device placement:
    searching the `Intrauterine`, `Device Insertion`, `Device Placement`,
    `Barrier` and `Contraceptive Device` label families returns only device
    entities (`NCIT:C42771` Intrauterine Device, `NCIT:C49838` Barrier Device,
    `NCIT:C42734` Contraceptive Device), dosage forms and routes of
    administration — none of them reachable from `NCIT:C25218` and so none of
    them valid for `treatment_term`. Rather than bind a device continuant where
    an action term is required, the action stays generic and
    `therapeutic_modality: DEVICE` carries the real signal.
  target_mechanisms:
  - target: Intrauterine Adhesion Formation and Cavity Obliteration
    treatment_effect: INHIBITS
    description: >-
      Physically separates the opposing raw surfaces so that fibrotic repair
      cannot bridge them.
  evidence:
  - reference: PMID:30936754
    reference_title: "Asherman's syndrome: current perspectives on diagnosis and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Use of intrauterine devices like balloon catheters or intrauterine
      contraceptive devices seems to be the preferred methods for the prevention
      of re-occurrence of adhesions after treatment.
    explanation: >-
      Supports barrier placement as the preferred adjunct, with the hedged
      wording ("seems to be") preserved.
  - reference: PMID:28582327
    reference_title: "A comprehensive review of Asherman's syndrome: causes, symptoms and treatment options."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Prevention of reformation of adhesions remains challenging and no single
      method for preventing recurrence has shown superiority.
    explanation: >-
      Retained as an explicit limit: the barrier approach is preferred by
      practice rather than by demonstrated superiority.
- name: Endometrial stem/progenitor cell therapy
  description: >-
    Investigational. Cell-based approaches aim to repopulate the regenerative
    compartment the disease destroys — the only strategy on this list that
    addresses the primary lesion rather than its consequences. It is curated
    here because it is the mechanistically matched intervention, not because it
    is established therapy; the evidence base remains preclinical and early
    clinical.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: stem cell therapy
    term:
      id: NCIT:C165194
      label: Stem Cell Therapy
  target_mechanisms:
  - target: Endometrial Epithelial Loss and Differentiation Signalling Failure
    treatment_effect: INHIBITS
    description: >-
      Restores a regenerative cell population capable of rebuilding endometrium,
      opposing the epithelial-loss arm.
  evidence:
  - reference: PMID:28582327
    reference_title: "A comprehensive review of Asherman's syndrome: causes, symptoms and treatment options."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cell-based therapies using endometrial stem/progenitor cells hold promise
      for future use in regenerating inadequate endometrium.
    explanation: >-
      Records the approach at the strength the source claims for it — promise
      for future use, not present efficacy — hence PARTIAL.
  - reference: PMID:30760192
    reference_title: "Endometrial Regeneration in Asherman's Syndrome: Clinical and Translational evidence of Stem Cell Therapies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Numerous studies have begun exploring the molecular mechanisms behind the
      fibrotic process underlying Asherman's Syndrome as well as the role of
      stem cells in the regeneration of the endometrium as a treatment modality.
    explanation: >-
      Records the existence and stage of the stem-cell approach as a treatment
      modality under investigation; the same review highlights current gaps in
      research, so nothing stronger is claimed.
- name: Antituberculous therapy for genital tuberculosis
  description: >-
    Where genital tuberculosis is the cause, antituberculous chemotherapy is the
    disease-directed treatment. It is included because it is the one etiology on
    this entry with an active, treatable upstream driver rather than a completed
    historical injury — and, unusually, menstrual function may partially return
    with treatment alone.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: antitubercular agent
      term:
        id: NCIT:C280
        label: Antitubercular Agent
  notes: >-
    `therapeutic_agent` is bound to the NCIT drug *class* rather than to the
    individual CHEBI first-line agents. Neither the cited case report nor the
    entry's other sources names a regimen — PMID:31388435 records only "9 months
    of antituberculous therapy" — so enumerating rifampicin/isoniazid/
    pyrazinamide/ethambutol would assert a composition the evidence does not
    state. CLAUDE.md permits an NCIT class term for exactly this case.
  target_mechanisms:
  - target: Endometrial Basal Layer Injury
    treatment_effect: INHIBITS
    description: >-
      Eradicating the mycobacterial infection removes the ongoing source of
      endometrial injury.
  evidence:
  - reference: PMID:31388435
    reference_title: "Case report of pelvic tuberculosis resulting in Asherman's syndrome and infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient was treated with 9 months of antituberculous therapy. While
      she has not yet succeeded in becoming pregnant, the patient has started to
      notice cyclic spotting, indicating possible return of menses.
    explanation: >-
      A single case with a partial menstrual response and no pregnancy — PARTIAL
      is the honest classification, and the snippet preserves the negative
      fertility outcome alongside the positive menstrual one.
progression:
- phase: Reproductive outcome after hysteroscopic adhesiolysis
  notes: >-
    Pooled across 54 studies and 4,640 women, roughly half conceive after
    adhesiolysis, but the pregnancies that follow are high-risk in a way that is
    mechanistically continuous with the disease: placenta accreta syndrome in
    about one in ten (10.1%) reflects implantation onto a scarred,
    basalis-deficient decidua, the same lesion that caused the infertility. The
    losses are also distributed across gestation rather than concentrated
    early — early pregnancy loss 17.7% and mid-trimester loss 11.5% — with
    cervical incompetence reported at 12.5% in the two studies that measured it.
    Ectopic pregnancy at 4.2% is the smallest of these. Antenatal surveillance
    for abnormal placentation is therefore part of the disease course, not an
    incidental precaution.
  evidence:
  - reference: PMID:30713131
    reference_title: "Reproductive outcomes after surgical treatment of asherman syndrome: A systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The pooled rate of pregnancy was 50.7%
    explanation: >-
      The pooled conception rate after adhesiolysis across 53 studies. Quoted as
      a short fragment because the confidence interval that follows it in the
      source is parenthesised as "(95% CI [confidence interval]: 49.1 to 52.3)",
      and the bracketed gloss is stripped from snippets before matching, so the
      longer quote cannot be verified verbatim.
  - reference: PMID:30713131
    reference_title: "Reproductive outcomes after surgical treatment of asherman syndrome: A systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    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: >-
      The five adverse-outcome rates quoted in this record, including the
      placenta accreta figure that motivates the antenatal-surveillance point.
  - reference: PMID:21437822
    reference_title: "Asherman's syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Follow-up studies to assure resolution of the scarring are mandatory
      before the patient attempts to conceive as is careful monitoring of
      pregnancies for cervical incompetence, placenta accreta, and intrauterine
      growth retardation.
    explanation: >-
      Supports the surveillance recommendation and names the same three
      pregnancy complications.
differential_diagnoses:
- name: Adenomyosis
  description: >-
    Also presents with abnormal menstruation, pelvic pain and impaired
    fertility, but the lesion is endometrial tissue within the myometrium rather
    than scar within the cavity, and the cavity itself is patent at
    hysteroscopy.
  distinguishing_features:
  - Uterine cavity patent at hysteroscopy, with no bridging fibrous bands
  - Junctional-zone thickening on MRI rather than cavity obliteration
- name: Endometriosis
  description: >-
    Shares cyclic pelvic pain and infertility. The direction of the relationship
    matters here: Asherman syndrome can cause endometriosis through obstructed
    retrograde menstruation, so the two may coexist as sequela rather than as
    alternatives.
  distinguishing_features:
  - Ectopic endometrial implants outside the uterus rather than intracavitary scar
- name: Hypothalamic or ovarian causes of secondary amenorrhea
  description: >-
    Amenorrhea from an outflow-tract lesion is distinguished from endocrine
    amenorrhea by a normal hormonal profile with absent withdrawal bleeding, and
    definitively by hysteroscopy.
  distinguishing_features:
  - Absent withdrawal bleeding despite adequate estrogen-progestin challenge
  - Normal gonadotropin and estradiol profile
discussions:
- discussion_id: mismatch_endmt_rat_model_only
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Does endothelial-to-mesenchymal transition contribute to the myofibroblast
    pool in human Asherman syndrome, or is it a feature of the rat
    mechanical-injury model?
  rationale: >-
    The EndMT arm rests entirely on a rat intrauterine adhesion model, where
    CD31/alpha-SMA double-positive cells appear in endometrium 14 days after
    injury. No human tissue confirmation was found in this curation pass. The
    mismatch is mechanistically meaningful rather than cosmetic: the human
    single-cell atlas of Asherman endometrium characterizes the disease niche in
    detail and emphasizes epithelial loss, so if EndMT were a major human
    myofibroblast source it might be expected to have surfaced there. Rodent IUA
    models are also made by acute mechanical or dual injury, which may recruit
    vascular remodelling responses that the slower human iatrogenic lesion does
    not.
  attaches_to:
  - pathophysiology#Myofibroblast Generation and Mesenchymal Activation
  proposed_experiments:
  - experiment_id: exp_ias_human_myofibroblast_origin
    name: Lineage-resolved myofibroblast origin in human Asherman endometrium
    description: >-
      Re-analyse or extend human Asherman single-cell/single-nucleus datasets
      for endothelial-mesenchymal intermediate states, and confirm with dual
      CD31/alpha-SMA immunofluorescence on Asherman hysteroscopic biopsies
      against matched controls, to quantify what fraction of the myofibroblast
      pool is endothelium-derived in human disease.
- discussion_id: gap_regeneration_versus_scarring_switch
  kind: KNOWLEDGE_GAP
  prompt: >-
    Why does the endometrium regenerate without scarring after menstruation and
    parturition, yet scar after curettage of the recently pregnant uterus?
  rationale: >-
    This is the central unanswered question of the disease and the reason the
    entry is modelled as a switch between repair programmes. The endometrium is
    an exemplar of scarless mammalian regeneration, including after the
    substantial tissue loss of childbirth, yet a comparatively minor iatrogenic
    insult in the same postpartum window produces permanent scar. Neither the
    depth of injury nor the pregnant state alone accounts for it, and
    identifying the determinant would be informative well beyond gynaecology —
    it is the question the regeneration literature explicitly poses of this
    tissue.
  attaches_to:
  - pathophysiology#Non-Regenerative Fibrotic Repair and Excessive ECM Deposition
  evidence:
  - reference: PMID:37843929
    reference_title: Mechanisms of Regeneration and Fibrosis in the Endometrium.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thus, the endometrium provides an exceptional platform to answer a central
      question of regenerative medicine: Why do some systems regenerate while
      others scar?
    explanation: >-
      The review poses this gap as an open question in exactly the terms used
      here, which is why it is recorded as a KNOWLEDGE_GAP rather than curated
      as a mechanism.
  proposed_experiments:
  - experiment_id: exp_ias_paired_injury_response_profiling
    name: Paired injury-response profiling across regenerative and scarring insults
    description: >-
      Profile the endometrial repair response after physiological shedding,
      postpartum involution, and instrumental evacuation in the same species and
      pregnancy state, to identify the divergence point at which the fibrotic
      programme is selected over the regenerative one.
- discussion_id: gap_prognosis_and_recurrence_prevention
  kind: KNOWLEDGE_GAP
  prompt: >-
    Can reproductive prognosis after adhesiolysis be predicted, and can
    recurrence be prevented?
  rationale: >-
    Two related failures of the current standard of care. There is no
    established method for predicting the likelihood of a live birth after
    treatment, and no adjunct has been shown superior for preventing adhesion
    reformation — which is the principal clinical problem, since recurrence
    rather than initial division is what limits outcomes. Both are recorded here
    because the treatment block would otherwise read as more settled than it is.
  attaches_to:
  - pathophysiology#Intrauterine Adhesion Formation and Cavity Obliteration
  evidence:
  - reference: PMID:39613882
    reference_title: Mechanistic insights into intrauterine adhesions.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Classical treatments have shown limited success, particularly in severe
      cases.
    explanation: >-
      The review's own assessment of current treatment. Its adjacent sentence on
      the prognostic gap is quoted here only in the rationale, because as
      published it reads "remains established" where the sense requires
      "unestablished", and an evidence snippet should not carry a claim whose
      literal wording contradicts it.
  - reference: PMID:28582327
    reference_title: "A comprehensive review of Asherman's syndrome: causes, symptoms and treatment options."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Prevention of reformation of adhesions remains challenging and no single
      method for preventing recurrence has shown superiority.
    explanation: >-
      Independent statement of the recurrence-prevention half of this gap.
  proposed_experiments:
  - experiment_id: exp_ias_live_birth_prognostic_model
    name: Prospective prognostic model for live birth after adhesiolysis
    description: >-
      Assemble a prospective multicentre cohort with standardized severity
      grading, residual endometrial thickness and second-look hysteroscopy, and
      derive and externally validate a live-birth prediction model.
  - experiment_id: exp_ias_anti_adhesion_adjunct_rct
    name: Head-to-head randomized comparison of anti-adhesion adjuncts
    description: >-
      Randomize balloon stent, intrauterine device, hyaluronic acid gel and no
      adjunct after adhesiolysis, with second-look hysteroscopy as the primary
      endpoint and live birth as a secondary endpoint.
- discussion_id: gap_postoperative_estrogen_benefit
  kind: KNOWLEDGE_GAP
  prompt: >-
    Does postoperative estrogen actually improve outcomes after adhesiolysis,
    and if the mechanism is real, why does the trial not detect a benefit?
  rationale: >-
    Postoperative estrogen is the one element of the standard regimen aimed at
    the regenerative failure rather than at the scar, and it is given on an
    explicit mechanistic rationale — drive proliferation of surviving
    endometrium across the denuded cavity. A randomised trial that simply
    withheld it found no increase in adhesion recurrence and no reduction in
    pregnancy or live-birth rates, while noting side effects. That is a gap
    rather than a settled negative: at least three readings remain open and the
    trial does not separate them. The regenerative substrate may be absent in
    the patients who most need it, so a proliferative drug has nothing to act
    on; the endogenous cycling estrogen of an ovulatory cohort may already
    saturate the receptor, leaving exogenous estrogen no margin; or epithelial
    proliferation may simply not be rate-limiting for the outcomes measured,
    which are dominated by recurrence of fibrosis. Recording it keeps the entry
    from presenting a contested adjunct as established care, and keeps the
    mechanism curated at the strength the evidence supports — plausible
    pharmacology, unproven benefit.
  attaches_to:
  - pathophysiology#Endometrial Epithelial Loss and Differentiation Signalling Failure
  evidence:
  - 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
    snippet: >-
      Usual care does not lead to better outcomes as compared with not giving
      exogenous estrogen but is associated with side effects.
    explanation: >-
      The trial's own conclusion, which is what opens the gap. It is cited as
      SUPPORT for the *existence* of the gap here, and separately as REFUTE
      against the benefit claim on the estrogen treatment entry.
  proposed_experiments:
  - experiment_id: exp_ias_estrogen_stratified_by_residual_endometrium
    name: Estrogen benefit stratified by residual functional endometrium
    description: >-
      Re-randomize or re-analyse post-adhesiolysis estrogen against no estrogen
      with patients stratified by residual endometrial thickness and by whether
      any basalis is identifiable at second-look hysteroscopy, to test whether a
      proliferative agent benefits only the subgroup that retains a substrate
      for it to act on.
  - experiment_id: exp_ias_estrogen_target_engagement
    name: Direct measurement of endometrial target engagement under estrogen
    description: >-
      Measure proliferation directly (endometrial thickness on serial
      ultrasound, Ki-67 index on second-look biopsy) in treated versus untreated
      arms, to establish whether the proliferative mechanism engages at all in
      this setting before attributing the null outcome result to it.
notes: >-
  Curated 2026-08-22 against issue #7837 (obstetric/gynaecologic coverage gap).
  The stub `stubs/Asherman_Syndrome.yaml` is deleted by the same change, with
  the lump/split call resolved as `DISEASE`.

  The entry was curated first from PubMed-retrieved primary literature and
  reviews, without a deep-research provider report; a DR run
  (`research/Asherman_Syndrome-deep-research-claude_code.md`, 15/15 references
  resolved, confabulation rate 0.0) was added afterwards at review request and
  cross-checked against the finished YAML. Its NEC preflight against
  MONDO:0015299 returns `SKIP` — MONDO records no causal gene for an acquired
  disease, so the gene-identity check cannot discriminate; the manual check
  passes (the report's top gene mentions are THBS1/SLPI/WNT7A/NOTCH2, all
  endometrial-fibrosis genes, and it carries no OMIM assertion to conflict
  with). The cross-check surfaced one substantive omission, now curated: the
  randomised trial of postoperative hormonal support (PMID:37396823), added as
  REFUTE evidence against the estrogen benefit claim and as the
  `gap_postoperative_estrogen_benefit` knowledge gap. Themes the report raised
  that are deliberately *not* curated here: hematometra as a separate phenotype
  (the report's own row is uncited, and the entry already carries the
  obstruction mechanism as `Menstrual Outflow Obstruction` feeding cyclic
  pelvic pain); the 3D-ultrasound diagnostic accuracy figures and the AFS/ESGE
  severity classifications (already listed below as second-pass work); the
  THBS1/PI3K-AKT and IGFBP3/5/6 anti-angiogenic molecular arms, which the
  report sources to reviews and preprints rather than to a quotable primary
  finding; and the single-cell GEO deposition, which needs
  `just verify-datasets` before any accession is asserted.

  Three modelling choices worth flagging for a reviewer. First, the three
  amplifier mechanisms (autophagy, ferroptosis, EndMT) are all deliberately kept
  off the canonical chain and expressed as `mechanistic_hypotheses` with
  `hypothesis_groups` on their edges, because each rests on a small patient
  observation plus rodent or in vitro perturbation; the shared upstream review
  (PMID:39613882) names exactly these three as the current pathogenesis
  frontier, which is corroboration of their salience but not of their causal
  status in human disease. Second, `HP:0000140 Abnormality of the menstrual
  cycle` is used for hypomenorrhea because HPO has no hypomenorrhea term —
  searched under `hypomenorrhea` and `menstr`. Third, the recurrent pregnancy
  loss phenotype is left ontology-unbound: `HP:0200067` exists and means exactly
  the right thing but is outside the `PhenotypeTerm` enum root, the recurring
  structural gap recorded as gap 3 of issue #7837. Both of the last two are the
  "no term beats a bad one" rule, applied once to a parent-term binding and once
  to omission.

  Endometrial receptivity biomarkers, the hysteroscopic severity classification
  systems (AFS/ESGE/March) as structured `definitions`, and the anti-adhesion
  gel barrier literature are all in scope for a second pass and are not curated
  here.
📚

References & Deep Research

Deep Research

1
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.

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