Ovarian Hyperstimulation Syndrome: Disease-Characteristics Report

Evidence cut-off: the search prioritized 2023–2024 publications, supplemented by earlier primary and systematic evidence where necessary. Evidence is labeled as human clinical, in vitro, animal-model, registry, or database evidence. OHSS-specific advanced-omics and quality-of-life literature remains sparse.

The table below summarizes the principal evidence suitable for knowledge-base ingestion.

Table: This table condenses the strongest gathered evidence on ovarian hyperstimulation syndrome across identifiers, epidemiology, mechanism, risk, phenotypes, prevention, management, trials, and genetics/models. It is designed to support rapid knowledge-base population while distinguishing established care from experimental approaches.

1. Disease information

Definition and scope

Ovarian hyperstimulation syndrome (OHSS) is an acute, predominantly iatrogenic systemic complication of controlled ovarian stimulation used in assisted reproductive technology (ART). It combines enlarged, multicystic ovaries with increased vascular permeability, intravascular volume depletion, and fluid accumulation in third spaces. Ascites is characteristic; pleural and occasionally pericardial effusions occur in severe disease. Rare spontaneous OHSS occurs without exogenous gonadotropin stimulation, usually during pregnancy in association with abnormal gonadotropin-receptor activation, very high hCG, or hypothyroidism. A concise 2024 definition describes OHSS as “a systemic condition marked by the enlargement of the ovaries and heightened vascular permeability.” (mares2024ovarianhyperstimulationsyndrome pages 2-3, mares2024ovarianhyperstimulationsyndrome pages 1-2)

Identifiers and synonyms

• MONDO: MONDO:0011972.
• MeSH: D016471, Ovarian Hyperstimulation Syndrome.
• Common names: ovarian hyperstimulation syndrome; OHSS; ovarian hyperstimulation syndrome following ovulation induction; spontaneous ovarian hyperstimulation syndrome, when no ovarian-stimulation drugs were used.
• OMIM/Orphanet: OHSS is not generally represented as a classical Mendelian disorder with a dedicated OMIM phenotype. Rare FSHR-related spontaneous OHSS is better represented through the causal gene/variant and clinical phenotype than as a uniform Mendelian disease.
• ICD: coding varies by jurisdiction and version; an exact ICD-10/ICD-11 code was not verified in the retrieved primary sources and should be validated directly against the target release before database ingestion.

Open Targets associates MONDO:0011972 most strongly with FSHR, followed by VEGFA, BRD2, KDR, LHCGR, and LHB; these are disease-target associations, not proof that each gene is monogenic-causal. (OpenTargets Search: ovarian hyperstimulation syndrome-FSHR,VEGFA,KDR,LHCGR)

The present report derives from aggregated disease-level resources, publications, and trial registries, not individual-level EHR data. The 2023 outcome study is a retrospective 15-patient case series and is explicitly identified where used. (alfaraj2023pregnancyoutcomesof pages 1-2)

2. Etiology, risk factors, and protective factors

Primary causal factors

The usual initiating sequence is:

1. Exogenous FSH/gonadotropin stimulation recruits many follicles.
2. Exogenous hCG used for final oocyte maturation—or endogenous hCG after implantation—activates luteinized follicles.
3. Luteinized granulosa cells produce excessive VEGF and other vasoactive mediators.
4. Endothelial barrier permeability rises, producing third-spacing and systemic complications. (mares2024ovarianhyperstimulationsyndrome pages 2-3, mares2024ovarianhyperstimulationsyndrome pages 1-2)

Thus, OHSS is generally treatment-triggered and mechanistically complex, rather than infectious, toxic, or a single-gene disease.

Clinical risk factors

Consistently reported factors are:

• PCOS or polycystic ovarian morphology;
• young reproductive age, often under 30–35 years;
• high antral follicle count and high ovarian reserve;
• elevated AMH;
• rapidly rising or high estradiol;
• numerous developing follicles and high oocyte yield;
• previous OHSS;
• hCG exposure and establishment of pregnancy, particularly multiple gestation;
• low BMI in some cohorts, although BMI is less consistent than ovarian-reserve markers. (mares2024ovarianhyperstimulationsyndrome pages 2-3, mares2024ovarianhyperstimulationsyndrome pages 1-2, NCT06333691 chunk 1)

Frequently used high-risk thresholds include AMH >3.4 ng/mL, peak estradiol >3,500 pg/mL, >25 follicles, or >24 oocytes. Trials have also used E2 >3,000–4,000 pg/mL and >20 follicles or retrieved oocytes. These are risk-stratification thresholds, not universal diagnostic criteria. (NCT06333691 chunk 1, NCT04351126 chunk 1, wu2022comparisonofthe pages 1-2)

Rare non-ART triggers include pregnancy-associated spontaneous disease, severe hypothyroidism, very high endogenous hCG, and functioning gonadotroph adenoma. A 2023 systematic review identified five reported patients who developed OHSS after long-acting GnRH agonist administration 3–5 days after controlled stimulation for fertility preservation; all recovered conservatively, but causality remains uncertain.

Genetic susceptibility and gene–environment interaction

Rare activating or sensitizing FSHR variants can permit hCG or TSH to activate FSHR, explaining spontaneous gestational OHSS. Common FSHR variants—including the linked codon 307/680 polymorphisms and Ser680Asn—and LHCGR rs4073366 have been associated with ovarian-response variability or OHSS susceptibility, but their predictive value is insufficient for routine clinical genotyping. (sun2022tie1contributesto pages 1-2, alviggi2018clinicalrelevanceof pages 15-16)

The principal gene–environment interaction is therefore receptor sensitivity × hormonal exposure: an FSHR/LHCGR genotype may alter response to administered FSH and hCG or to pregnancy-associated hCG. PCOS/high ovarian reserve supplies a highly responsive follicle pool, while the stimulation regimen supplies the environmental/pharmacological trigger.

Protective factors

Protective clinical strategies include individualized lower gonadotropin exposure, GnRH-antagonist stimulation, GnRH-agonist rather than hCG trigger where appropriate, avoiding unnecessary hCG luteal support, and freeze-all embryo cryopreservation in high responders. These are preventive interventions rather than intrinsic environmental factors. No validated protective allele, diet, exercise regimen, or occupational/environmental exposure has been established specifically for OHSS. (mares2024ovarianhyperstimulationsyndrome pages 1-2, wu2022comparisonofthe pages 1-2)

3. Phenotypes

OHSS occurs in reproductive-age adults after stimulation or during pregnancy. Severity is variable and the course is acute/episodic rather than lifelong.

• Ovarian enlargement/multicystic ovaries: bilateral in typical stimulation-associated disease; ultrasound may show ovaries 5–12 cm or larger. Suggested HPO: Enlarged ovary, Ovarian cyst.
• Abdominal distension, discomfort, or severe pain: very common across symptomatic grades; impairs mobility, sleep, eating, and work. Suggested HPO: Abdominal distension, Abdominal pain.
• Nausea, vomiting, diarrhea: mild-to-severe gastrointestinal symptoms. Suggested HPO: Nausea, Vomiting, Diarrhea.
• Ascites: ultrasound-only in moderate disease; clinically tense or massive in severe disease. Suggested HPO: Ascites.
• Rapid weight gain/peripheral edema: reflects fluid redistribution. Suggested HPO: Abnormal weight gain, Peripheral edema, Anasarca.
• Dyspnea, pleural effusion, hypoxemia: severe respiratory involvement. Suggested HPO: Dyspnea, Pleural effusion, Hypoxemia.
• Oliguria/acute kidney injury: caused primarily by reduced effective circulating volume and renal perfusion. Suggested HPO: Oliguria, Acute kidney injury.
• Hemoconcentration and leukocytosis: severe criteria commonly include hematocrit >45% and WBC >15,000/mm³. Suggested HPO: Hemoconcentration, Leukocytosis.
• Electrolyte/acid-base abnormalities: dilutional hyponatremia, hyperkalemia, and metabolic acidosis may occur. Suggested HPO: Hyponatremia, Hyperkalemia, Metabolic acidosis.
• Hepatic dysfunction: AST/ALT elevation occurs in approximately 30% of severe cases in the reviewed literature. Suggested HPO: Elevated hepatic transaminase.
• Thrombosis: deep venous thrombosis, pulmonary embolism, and unusual-site thromboses can occur. Suggested HPO: Venous thrombosis, Pulmonary embolism.
• Neurologic/critical manifestations: altered mental status, cerebral edema, respiratory failure, abdominal compartment syndrome, or multiorgan failure are rare. (mares2024ovarianhyperstimulationsyndrome pages 3-5, alfaraj2023pregnancyoutcomesof pages 2-3)

Formal per-phenotype frequencies are poorly standardized because studies use different classifications and preventive protocols. Disease-specific EQ-5D, SF-36, or PROMIS estimates were not identified. Nevertheless, pain, distension, vomiting, dyspnea, repeated monitoring, hospitalization, invasive drainage, and treatment-cycle interruption plausibly produce substantial short-term quality-of-life burden.

4. Genetic and molecular information

Causal and susceptibility genes

FSHR is the best-supported causal gene in rare spontaneous OHSS. Reported mechanisms generally involve germline gain of abnormal sensitivity to hCG or TSH. OHSS is not routinely caused by FSHR loss of function. Exact HGVS variants, ClinVar classifications, and population frequencies were not recoverable from the retrieved full texts; they should be curated case-by-case from the original reports before a pathogenic-variant table is populated.

LHCGR variants may modify controlled-stimulation response. VEGFA/KDR, TIE1, EGR1, LHB, and possibly BRD2 are mechanistic or association targets, not established high-penetrance causal genes for ordinary iatrogenic OHSS. Open Targets lists literature-backed associations for FSHR (five evidence records), VEGFA (five), LHCGR (three), KDR (one), LHB (two), and BRD2 (three). (OpenTargets Search: ovarian hyperstimulation syndrome-FSHR,VEGFA,KDR,LHCGR)

Functional consequences

• FSHR sensitizing variants: receptor gain of inappropriate responsiveness to hCG/TSH.
• hCG–LHCGR signaling: induces luteinization and vasoactive-factor production.
• VEGFA–KDR/VEGFR2: increases endothelial permeability.
• EGR1–TIE1–PI3K–AKT: experimentally increases granulosa-cell VEGF; TIE1 knockdown attenuated induced OHSS in rats. (sun2022tie1contributesto pages 1-2, sun2022tie1contributesto pages 7-9)

No recurrent pathogenic chromosomal abnormality, somatic driver, founder mutation, anticipation, germline mosaicism pattern, or established carrier frequency defines OHSS. Routine ACMG-style interpretation is relevant only when evaluating a rare suspected spontaneous FSHR-mediated case.

Pharmacogenomics, modifiers, and epigenetics

A 2018 meta-analysis found that gonadotropin/receptor genotypes affect ovarian-response measures, supporting pharmacogenomic plausibility, but concluded that further study was required before clinical implementation. No CPIC/PharmGKB-style prescribing guideline for OHSS prevention was identified. (alviggi2018clinicalrelevanceof pages 15-16)

OHSS-specific causal DNA-methylation, histone, chromatin, or validated epigenetic biomarker evidence was not established in the retrieved literature.

5. Environmental and lifestyle information

The dominant non-genetic exposure is medical gonadotropin treatment, especially hCG exposure in a high responder. No convincing evidence identifies pollution, radiation, occupational agents, smoking, alcohol, diet, or exercise as direct OHSS causes. Lifestyle modification can improve broader PCOS and fertility-treatment health but is not an acute OHSS treatment. No bacterial, viral, fungal, or parasitic trigger is recognized.

6. Mechanism and pathophysiology

Integrated causal chain

Upstream trigger: multifollicular development followed by hCG/LHCGR signaling in luteinized granulosa cells.

Intermediate ovarian signaling: increased VEGFA, angiopoietin/TIE signaling, EGR1/TIE1/PI3K–AKT activation, and contribution from IL-6, IL-8, platelet-activating factor, and ovarian renin–angiotensin-system components.

Endothelial effect: VEGF activates KDR/VEGFR2 on endothelial cells, loosening intercellular junctions and increasing transendothelial transport.

Systemic physiology: protein-rich fluid leaves the vascular compartment and accumulates in peritoneal, pleural, and occasionally pericardial spaces. Effective hypovolemia produces RAAS activation, tachycardia, oliguria, renal injury, and electrolyte abnormalities. Hemoconcentration, thrombocytosis, elevated fibrinogen, immobility, and pregnancy produce a prothrombotic state.

Clinical manifestations: enlarged painful ovaries, ascites and distension; intestinal edema, nausea, ileus; pleural effusion and dyspnea; renal and hepatic dysfunction; thrombosis and, rarely, multiorgan failure. (mares2024ovarianhyperstimulationsyndrome pages 2-3, mares2024ovarianhyperstimulationsyndrome pages 3-5)

The strongest recent functional study found elevated TIE1 and VEGF in granulosa cells from patients and induced-OHSS rats. hCG induced TIE1 through PI3K/AKT; EGR1 bound the TIE1 promoter; TIE1 silencing abolished hCG-induced VEGF in SVOG cells and reduced ovarian weight, corpora lutea, and VEGF in rats. The abstract states: “Tie1 silencing abolished the hCG-induced VEGF level in SVOG cells and attenuated the progression of OHSS in rats.” This is compelling mechanistic evidence but not yet a validated human therapy. (sun2022tie1contributesto pages 1-2, sun2022tie1contributesto pages 2-3, sun2022tie1contributesto pages 7-9)

Ontology suggestions

• GO biological processes: response to gonadotropin; ovarian follicle development; angiogenesis (GO:0001525); blood-vessel development (GO:0001568); regulation of vascular permeability (GO:0043114); PI3K signaling; inflammatory response; coagulation; fluid homeostasis.
• Cell Ontology: ovarian granulosa cell; granulosa-lutein cell; vascular endothelial cell; luteal cell.
• Proteins/genes: LHCGR, FSHR, VEGFA, KDR, TIE1, EGR1.

Molecular profiling and advanced technologies

Targeted expression and protein assays support VEGF/TIE1/EGR1 dysregulation. However, no sufficiently replicated OHSS-specific diagnostic transcriptomic, proteomic, metabolomic, lipidomic, single-cell, spatial-transcriptomic, CRISPR-screen, or integrated multi-omics signature was identified. These should be recorded as research gaps, not negative findings.

7. Anatomical structures affected

• Primary organ: ovaries—typically bilateral, especially after controlled stimulation. UBERON suggestion: ovary (UBERON:0000992).
• Primary tissue/cells: ovarian follicles, granulosa and granulosa-lutein cells, corpora lutea, ovarian vasculature.
• Secondary compartments: peritoneal cavity/ascitic space; pleural cavity; rarely pericardial cavity.
• Secondary organs: kidneys, lungs, liver, bowel, and venous circulation through hypovolemia, edema, congestion, and thrombosis.
• Systems: reproductive/endocrine, vascular, renal, respiratory, gastrointestinal, hepatic, and hematologic.
• Subcellular/signaling localization: plasma-membrane receptors FSHR, LHCGR, VEGFR2/KDR and TIE1; cytoplasmic PI3K–AKT signaling; nuclear EGR1-mediated transcription. Suggested GO cellular components: plasma membrane, receptor complex, cytoplasm, nucleus, cell–cell junction.

8. Temporal development

OHSS is adult-onset and acute. Early OHSS generally begins within nine days after oocyte retrieval/hCG trigger and is driven primarily by exogenous hCG. Late OHSS begins around day 10 or later and is driven or prolonged by endogenous pregnancy hCG. The Australian cohort reported 1.2% early and 0.9% late OHSS. (mares2024ovarianhyperstimulationsyndrome pages 1-2, NCT02620605 chunk 1)

The syndrome progresses over days from abdominal symptoms and ovarian enlargement to ascites and systemic abnormalities. Without pregnancy, it is usually self-limited as luteal activity declines. Pregnancy can prolong or exacerbate disease. Clinical-trial outcome windows assess regression over approximately 2–21 days, although critical disease may require longer hospitalization. (NCT02392520 chunk 1)

The critical intervention window is before hCG trigger, when ovarian response is apparent and trigger choice, dose modification, coasting, or freeze-all can still prevent severe disease.

9. Inheritance and population epidemiology

Modern estimates are cycle-based rather than population prevalence estimates:

• Danish cohort: 1.2% annual incidence, 186,168 cycles.
• Chinese nationwide cohort: 1.14% mean annual incidence, 1,581,703 cycles, with a declining trend.
• Australian prospective antagonist-protocol cohort: 2.1% overall, including 1.2% early and 0.9% late OHSS.
• Older systematic evidence reported moderate OHSS in approximately 3–6% and severe OHSS in 0.2–1% of cycles; registry protocols cite severe rates up to 0.1–3%, reflecting heterogeneous eras and definitions. (guo2016pharmacologicinterventionsin pages 1-2, mares2024ovarianhyperstimulationsyndrome pages 1-2, NCT03996434 chunk 1)

The affected population is almost exclusively females undergoing ovarian stimulation or pregnant females with rare spontaneous disease; a male:female ratio is therefore not meaningful. Geographic variation primarily reflects ART access, patient selection, stimulation practices, reporting, and classification rather than endemic biology.

Ordinary iatrogenic OHSS has multifactorial susceptibility, not Mendelian inheritance. Rare FSHR-mediated spontaneous disease is germline and may show dominant functional effects, but penetrance and expressivity depend strongly on pregnancy and hormonal exposure. Founder effects, consanguinity, carrier frequency, and anticipation are not established disease-level characteristics.

10. Diagnostics

Clinical diagnosis and severity

Diagnosis is clinical and is anchored to recent ovarian stimulation or pregnancy, ovarian enlargement, symptoms, ascites, and laboratory evidence of hemoconcentration or organ dysfunction. Golan-type systems grade mild, moderate, and severe disease; Navot-type systems add objective laboratory and respiratory criteria and a critical category. (mares2024ovarianhyperstimulationsyndrome pages 2-3, mares2024ovarianhyperstimulationsyndrome pages 3-5)

Representative criteria include:

• Mild: bloating/mild pain, enlarged ovaries.
• Moderate: nausea/vomiting and ultrasound ascites.
• Severe: massive ascites or hydrothorax, dyspnea, oliguria, Hct >45%, WBC >15,000/mm³, creatinine elevation, hepatic dysfunction, or anasarca.
• Critical: thrombosis, respiratory failure, severe renal failure, hemodynamic instability, or multiorgan failure. (mares2024ovarianhyperstimulationsyndrome pages 3-5, NCT02620605 chunk 1)

Tests

• Ultrasound: transvaginal ultrasound for ovarian size/cysts and pelvic ascites; abdominal or thoracic imaging if extensive fluid is suspected.
• Blood: CBC/hematocrit, electrolytes, urea/creatinine, liver enzymes, albumin/total protein, coagulation studies where indicated.
• Monitoring: weight, abdominal circumference, vital signs, oxygen saturation, fluid balance, and urine output.
• Pregnancy testing/hCG: distinguishes pregnancy-associated persistence and informs the early/late phenotype.
• Biomarkers: AMH, AFC, estradiol, follicle number, and oocyte yield are useful risk predictors; VEGF is mechanistically important but not a validated routine diagnostic test.

Differential diagnosis

Exclude ovarian torsion or rupture, ectopic or heterotopic pregnancy, intra-abdominal bleeding, pelvic infection, appendicitis, gastroenteritis, pulmonary embolism, pneumonia, heart/liver/renal disease causing effusions, and ovarian malignancy when the history or course is atypical.

Genetic and omics testing

Routine genetic testing is not recommended for stimulation-associated OHSS. In recurrent or spontaneous OHSS—especially with hypothyroidism, unexpectedly low hCG, or familial recurrence—targeted FSHR sequencing or an appropriate receptor-signaling panel may be considered in a specialist/research setting. WES/WGS may help unresolved exceptional cases, but there is no validated diagnostic yield. CMA, karyotype, FISH, mitochondrial testing, and repeat-expansion testing have no routine role. No omics-based clinical diagnostic is validated.

11. Outcome and prognosis

Most mild and moderate cases recover completely with monitoring and supportive care. Severe disease can cause hospitalization, invasive drainage, thromboembolism, acute kidney injury, respiratory failure, ovarian torsion, hepatic dysfunction, or critical illness. Mortality is rare in contemporary care, but the retrieved sources did not provide a sufficiently current population mortality estimate. There is no relevant five- or ten-year survival metric because OHSS is an acute syndrome. (mares2024ovarianhyperstimulationsyndrome pages 1-2, mares2024ovarianhyperstimulationsyndrome pages 3-5)

A 2023 single-center case series of 15 women reported pregnancy in 73.3%; 73.3% had severe OHSS. Deliveries were frequently preterm: 33.3% at 32–37 weeks, 33.3% at 28–32 weeks, and 6.7% before 28 weeks. These estimates should not be generalized because of small sample size, severity-enriched selection, and retrospective design. Larger literature is inconsistent concerning miscarriage, hypertensive disorders, gestational diabetes, and fetal growth. (alfaraj2023pregnancyoutcomesof pages 1-2, alfaraj2023pregnancyoutcomesof pages 7-8)

Poor prognostic indicators include rising hematocrit, worsening ascites/pleural effusion, oliguria, creatinine or liver-test deterioration, hypoxemia, thromboembolic symptoms, pregnancy-associated late disease, and inability to maintain oral intake.

12. Treatment

Management algorithm

1. Mild disease: outpatient counseling, oral hydration according to thirst, analgesia/antiemetics as appropriate, avoidance of strenuous activity and intercourse because enlarged ovaries are torsion-prone, weight/abdominal girth and urine-output monitoring, and rapid reassessment for deterioration.
2. Moderate disease: closer laboratory and ultrasound monitoring; assess thrombosis risk and oral intake.
3. Severe/critical disease: hospitalize when clinically indicated; restore effective circulating volume cautiously, correct electrolyte abnormalities, monitor renal/respiratory/hepatic status, provide thromboprophylaxis unless contraindicated, and drain tense symptomatic ascites by ultrasound-guided paracentesis. Pleural drainage or intensive care may be required for respiratory compromise. (mares2024ovarianhyperstimulationsyndrome pages 3-5, NCT02392520 chunk 1)

The goal is supportive stabilization while ovarian vasoactive activity resolves; no drug reliably reverses established OHSS immediately.

Pharmacologic and procedural interventions

• Cabergoline: dopamine agonist that inhibits VEGFR2 phosphorylation; best supported as prophylaxis in high-risk cycles rather than rescue treatment.
• Metformin: may lower OHSS risk in PCOS, particularly in agonist protocols; it is not a universal OHSS drug.
• GnRH antagonist/cetrorelix: luteal re-initiation for established early disease is promising but not universally standard. A 48-woman randomized study used cetrorelix 0.25 mg/day for three days after retrieval with embryo freezing; sequential E2 tracked response better than ovarian diameter. NCT02823080. (salama2017sequentiale2levels pages 1-2)
• Paracentesis: relieves tense ascites, dyspnea, pain, and renal compromise; suggested NCIT concept: Paracentesis.
• Albumin: may be used selectively for intravascular support in established severe disease, but routine prophylactic albumin is not supported and may reduce pregnancy rate.
• Anticoagulation: risk-based prophylaxis for severe OHSS, hospitalization, immobility, or pregnancy; drug and duration should follow local obstetric/hematology guidance.

Suggested NCIT intervention concepts include ovarian-stimulation protocol modification, embryo cryopreservation, cabergoline therapy, intravenous-fluid therapy, paracentesis, thromboprophylaxis, hospitalization, and intensive-care treatment.

Preventive-drug efficacy

A 2022 network meta-analysis found reductions in moderate-to-severe OHSS with calcium (RR 0.14, 95% CI 0.04–0.46), hydroxyethyl starch (RR 0.25, 0.07–0.73), and cabergoline (RR 0.43, 0.24–0.71), without detected effects on pregnancy, miscarriage, or live birth; calcium ranked highest by SUCRA at 92.4%. An earlier 31-RCT/7,181-participant network analysis also reported benefit for aspirin, calcium, cabergoline, metformin, and HES, while prophylactic albumin reduced pregnancy rate (RR 0.85, 0.74–0.97). HES safety concerns in other clinical contexts and heterogeneity among older trials mean these rankings should not supersede contemporary reproductive-society protocols. (wu2022comparisonofthe pages 1-2, guo2016pharmacologicinterventionsin pages 1-2, guo2016pharmacologicinterventionsin pages 7-9)

Experimental clinical research

• NCT06333691: completed randomized prevention study, 180 high-risk women; calcium gluconate+diosmin, cabergoline, and cabergoline+diosmin. Registry posted March 27, 2024; a derived 2025 publication is listed. (NCT06333691 chunk 1)
• NCT04351126: completed phase 2, 107 participants; fludrocortisone added to conventional therapy or used prophylactically under a “defective mineralocorticoid response” hypothesis. This is not established care. (NCT04351126 chunk 1)
• NCT03996434: completed phase 4, 300 participants; coasting versus cetrorelix in high-risk women. (NCT03996434 chunk 1)
• NCT05198128: proposed quadruple-masked calcium-gluconate trial, estimated 200 participants; registry status unknown. (NCT05198128 chunk 1)
• NCT02670304: completed phase 4, 100 participants; letrozole versus aspirin after retrieval. (NCT02670304 chunk 1)
• NCT03794037: montelukast plus dydrogesterone in freeze-all cycles; suspended for lack of funding, estimated n=20. (NCT03794037 chunk 1)
• NCT02392520: planned luteal cetrorelix versus conventional treatment for severe early OHSS; registry status unknown. (NCT02392520 chunk 1)

Gene therapy, cell therapy, RNA therapy, genome editing, and immunotherapy have no current clinical role.

13. Prevention

Primary prevention

• Assess AMH, AFC, PCOS, age, prior response/OHSS, and baseline ultrasound.
• Individualize gonadotropin dose and avoid excessive stimulation.
• Prefer a GnRH-antagonist protocol for high-risk patients.
• Use a GnRH-agonist trigger instead of hCG when clinically appropriate.
• Avoid or minimize additional hCG luteal support.
• Use cabergoline selectively in high-risk cycles.
• Consider metformin in appropriate patients with PCOS.
• Cancel or modify the cycle if risk becomes unacceptable. (mares2024ovarianhyperstimulationsyndrome pages 1-2, wu2022comparisonofthe pages 1-2)

Secondary prevention

When excessive response is already evident, use coasting/withholding gonadotropins, alter trigger strategy, intensive monitoring, and freeze all embryos to avoid pregnancy-driven late OHSS. Cryopreservation is a real-world prevention strategy, although rare OHSS can still occur after agonist trigger/freeze-all.

Tertiary prevention

Early symptom recognition, structured outpatient monitoring, prompt laboratory reassessment, thrombosis-risk evaluation, careful volume management, and timely paracentesis prevent progression and organ complications.

No vaccine, infectious prophylaxis, newborn screening, population screening, carrier screening, or public-health environmental intervention applies. Counseling before stimulation should explain warning symptoms, emergency contact pathways, and the possibility of cycle modification or deferred transfer.

14. Other species and natural disease

OHSS is primarily a human iatrogenic syndrome. No well-established, routinely recognized naturally occurring veterinary counterpart or zoonotic process was identified. Domestic mammals can develop ovarian enlargement or gonadotropin-related reproductive abnormalities, but these should not automatically be labeled natural OHSS without species-specific evidence. There is no transmission or zoonotic potential.

Relevant orthologous pathways—FSHR/LHCGR, VEGFA/KDR, TIE1, and PI3K–AKT—are conserved across mammals. Suggested model taxa are Rattus norvegicus (NCBI Taxonomy 10116) and Mus musculus (10090).

15. Model organisms and experimental systems

Induced rat models

Immature or cycling rats are treated with gonadotropins followed by hCG to reproduce ovarian enlargement, increased corpora lutea, VEGF elevation, vascular leakage, and ascites. In Sun et al., induced rats showed increased ovarian TIE1 and VEGF, while TIE1 knockdown reduced ovarian weight, corpora lutea, and VEGF. These models are useful for causal signaling and permeability studies. Their limitations include pharmacologically compressed timing, species-specific ovarian physiology, and incomplete reproduction of human pregnancy, thrombosis, critical-care complications, and heterogeneous ART protocols. (sun2022tie1contributesto pages 1-2, sun2022tie1contributesto pages 7-9)

Human cellular systems

Primary granulosa cells from women with OHSS and the non-tumorigenic human granulosa-lutein SVOG line are used with acute hCG stimulation. RT-qPCR, immunoblotting, promoter binding, silencing, and pathway inhibition support the EGR1→TIE1→PI3K/AKT→VEGF chain. Endothelial-cell systems are appropriate for permeability assays but do not reproduce the endocrine-organ context. (sun2022tie1contributesto pages 2-3)

Genetic models and resources

No standardized commercial FSHR knock-in OHSS model was established in the retrieved evidence. Candidate research resources include MGI/IMSR for receptor or VEGF-pathway mouse lines, RGD for rat models, Cellosaurus for granulosa-cell lines, and GEO/ArrayExpress for exploratory expression datasets. Organoid, iPSC, single-cell, and spatial models remain emerging rather than validated OHSS standards.

Overall interpretation and research gaps

Current expert understanding treats OHSS as a preventable, hCG-dependent vascular-permeability syndrome originating in an excessively luteinized ovary. The strongest evidence supports risk-adapted stimulation, antagonist protocols, agonist triggering, freeze-all strategies, and selective dopamine-agonist prophylaxis. VEGF/VEGFR2 is the central effector pathway, while EGR1–TIE1–PI3K–AKT is a promising upstream mechanism requiring clinical validation. (mares2024ovarianhyperstimulationsyndrome pages 2-3, wu2022comparisonofthe pages 1-2, sun2022tie1contributesto pages 1-2)

Priority gaps are standardized international severity criteria; contemporary population mortality and quality-of-life estimates; externally validated risk models across ancestries and ART protocols; rigorous evaluation of rare FSHR variants; and replicated single-cell, spatial, proteomic, metabolomic, and multi-omic studies. Experimental calcium/diosmin, mineralocorticoid, montelukast, letrozole, and luteal-antagonist strategies should not be represented as established therapies until adequately replicated.

Key URLs and publication dates

• Mareș & Petca, Ovarian hyperstimulation syndrome, 2024: https://doi.org/10.26416/obsgin.72.4.2024.10891 (mares2024ovarianhyperstimulationsyndrome pages 2-3)
• Sun et al., Experimental & Molecular Medicine, January 2022: https://doi.org/10.1038/s12276-021-00722-8 (sun2022tie1contributesto pages 1-2)
• Wu et al., Frontiers in Endocrinology, 2022: https://doi.org/10.3389/fendo.2022.808517 (wu2022comparisonofthe pages 1-2)
• Guo et al., Scientific Reports, January 2016: https://doi.org/10.1038/srep19093 (guo2016pharmacologicinterventionsin pages 1-2)
• Alfaraj et al., Cureus, July 2023: https://doi.org/10.7759/cureus.42303 (alfaraj2023pregnancyoutcomesof pages 1-2)
• Salama et al., BMC Women’s Health, November 2017: https://doi.org/10.1186/s12905-017-0466-z; NCT02823080 (salama2017sequentiale2levels pages 1-2)

References

1. (OpenTargets Search: ovarian hyperstimulation syndrome-FSHR,VEGFA,KDR,LHCGR): Open Targets Query (ovarian hyperstimulation syndrome-FSHR,VEGFA,KDR,LHCGR, 13 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

2. (mares2024ovarianhyperstimulationsyndrome pages 1-2): Alina Mareș and Aida Petca. Ovarian hyperstimulation syndrome. Obstetrica şi Ginecologia, 2024. URL: https://doi.org/10.26416/obsgin.72.4.2024.10891, doi:10.26416/obsgin.72.4.2024.10891. This article has 0 citations.

3. (NCT06333691 chunk 1): Aya Mohammed Abdallah. Comparative Study Between Calcium Gluconate With Diosmin, Cabergoline and Cabergoline With Diosmin. Minia University. 2022. ClinicalTrials.gov Identifier: NCT06333691

4. (sun2022tie1contributesto pages 1-2): Lihua Sun, Hui Tian, Songguo Xue, Hongjuan Ye, Xue Xue, Rongxiang Wang, Yu Liu, Caixia Zhang, Qiuju Chen, and Shaorong Gao. Tie1 contributes to the development of ovarian hyperstimulation syndrome under the regulation of egr1 in granulosa cells. Experimental & Molecular Medicine, 54:81-90, Jan 2022. URL: https://doi.org/10.1038/s12276-021-00722-8, doi:10.1038/s12276-021-00722-8. This article has 3 citations and is from a peer-reviewed journal.

5. (sun2022tie1contributesto pages 2-3): Lihua Sun, Hui Tian, Songguo Xue, Hongjuan Ye, Xue Xue, Rongxiang Wang, Yu Liu, Caixia Zhang, Qiuju Chen, and Shaorong Gao. Tie1 contributes to the development of ovarian hyperstimulation syndrome under the regulation of egr1 in granulosa cells. Experimental & Molecular Medicine, 54:81-90, Jan 2022. URL: https://doi.org/10.1038/s12276-021-00722-8, doi:10.1038/s12276-021-00722-8. This article has 3 citations and is from a peer-reviewed journal.

6. (wu2022comparisonofthe pages 1-2): Di Wu, Hao Shi, Yiping Yu, Ting Yu, and Jun Zhai. Comparison of the effectiveness of various medicines in the prevention of ovarian hyperstimulation syndrome: a network meta-analysis of randomized controlled trials. Frontiers in Endocrinology, Jan 2022. URL: https://doi.org/10.3389/fendo.2022.808517, doi:10.3389/fendo.2022.808517. This article has 21 citations.

7. (salama2017sequentiale2levels pages 1-2): Khalid M. Salama, Hesham M. Abo Ragab, Mohammed F. El Sherbiny, Ali A. Morsi, and Ibrahim I. Souidan. Sequential e2 levels not ovarian maximal diameter estimates were correlated with outcome of cetrotide therapy for management of women at high-risk of ovarian hyperstimulation syndrome: a randomized controlled study. BMC Women's Health, Nov 2017. URL: https://doi.org/10.1186/s12905-017-0466-z, doi:10.1186/s12905-017-0466-z. This article has 8 citations.

8. (NCT04351126 chunk 1): Muhammad saber mahmoud sayed zeafan. Management of Ovarian Hyperstimulation Syndrome as a State of Defective Mineralocorticoid Response. Ganin Fertility Center. 2019. ClinicalTrials.gov Identifier: NCT04351126

9. (NCT02620605 chunk 1): Mona M Shaban. The Influence of Timing of Cabergoline Initiation on Prevention of OHSS. Mona M Shaban. 2017. ClinicalTrials.gov Identifier: NCT02620605

10. (mares2024ovarianhyperstimulationsyndrome pages 3-5): Alina Mareș and Aida Petca. Ovarian hyperstimulation syndrome. Obstetrica şi Ginecologia, 2024. URL: https://doi.org/10.26416/obsgin.72.4.2024.10891, doi:10.26416/obsgin.72.4.2024.10891. This article has 0 citations.

11. (NCT02392520 chunk 1): Luteal Antagonist Versus Conventional Treatment in Women With Severe Early Ovarian Hyperstimulation Syndrome (OHSS). Eugonia. 2015. ClinicalTrials.gov Identifier: NCT02392520

12. (guo2016pharmacologicinterventionsin pages 1-2): Jun-Liang Guo, Duo-Duo Zhang, Yue Zhao, Dan Zhang, Xi-Meng Zhang, Can-Quan Zhou, and Shu-Zhong Yao. Pharmacologic interventions in preventing ovarian hyperstimulation syndrome: a systematic review and network meta-analysis. Scientific Reports, Jan 2016. URL: https://doi.org/10.1038/srep19093, doi:10.1038/srep19093. This article has 48 citations and is from a peer-reviewed journal.

13. (guo2016pharmacologicinterventionsin pages 7-9): Jun-Liang Guo, Duo-Duo Zhang, Yue Zhao, Dan Zhang, Xi-Meng Zhang, Can-Quan Zhou, and Shu-Zhong Yao. Pharmacologic interventions in preventing ovarian hyperstimulation syndrome: a systematic review and network meta-analysis. Scientific Reports, Jan 2016. URL: https://doi.org/10.1038/srep19093, doi:10.1038/srep19093. This article has 48 citations and is from a peer-reviewed journal.

14. (NCT03996434 chunk 1): Coasting Versus Antagonist Protocol in Patients at High Risk of OHSS. ClinAmygate. 2019. ClinicalTrials.gov Identifier: NCT03996434

15. (NCT03794037 chunk 1): Ahmed Saad. Montelukast for Prevention & Treatment of OHSS. Benha University. 2018. ClinicalTrials.gov Identifier: NCT03794037

16. (NCT02670304 chunk 1): Zhou Canquan. Preventive Application of Letrozole Decrease Incidence of Early Onset of OHSS. First Affiliated Hospital, Sun Yat-Sen University. 2012. ClinicalTrials.gov Identifier: NCT02670304

17. (sun2022tie1contributesto pages 7-9): Lihua Sun, Hui Tian, Songguo Xue, Hongjuan Ye, Xue Xue, Rongxiang Wang, Yu Liu, Caixia Zhang, Qiuju Chen, and Shaorong Gao. Tie1 contributes to the development of ovarian hyperstimulation syndrome under the regulation of egr1 in granulosa cells. Experimental & Molecular Medicine, 54:81-90, Jan 2022. URL: https://doi.org/10.1038/s12276-021-00722-8, doi:10.1038/s12276-021-00722-8. This article has 3 citations and is from a peer-reviewed journal.

18. (alviggi2018clinicalrelevanceof pages 15-16): Carlo Alviggi, Alessandro Conforti, Daniele Santi, Sandro C Esteves, Claus Yding Andersen, Peter Humaidan, Paolo Chiodini, Giuseppe De Placido, and Manuela Simoni. Clinical relevance of genetic variants of gonadotrophins and their receptors in controlled ovarian stimulation: a systematic review and meta-analysis. Human Reproduction Update, 24:599–614, Jun 2018. URL: https://doi.org/10.1093/humupd/dmy019, doi:10.1093/humupd/dmy019. This article has 137 citations and is from a highest quality peer-reviewed journal.

19. (alfaraj2023pregnancyoutcomesof pages 1-2): Samaher Alfaraj, Ashwaq A Alharbi, Hind J Aldabal, Yara S Alhabib, and Shihanah AlKhelaiwi. Pregnancy outcomes of assisted reproductive technology (art) cycle complicated by ovarian hyperstimulation syndrome (ohss): case series study. Cureus, Jul 2023. URL: https://doi.org/10.7759/cureus.42303, doi:10.7759/cureus.42303. This article has 6 citations.

20. (alfaraj2023pregnancyoutcomesof pages 7-8): Samaher Alfaraj, Ashwaq A Alharbi, Hind J Aldabal, Yara S Alhabib, and Shihanah AlKhelaiwi. Pregnancy outcomes of assisted reproductive technology (art) cycle complicated by ovarian hyperstimulation syndrome (ohss): case series study. Cureus, Jul 2023. URL: https://doi.org/10.7759/cureus.42303, doi:10.7759/cureus.42303. This article has 6 citations.

21. (mares2024ovarianhyperstimulationsyndrome pages 2-3): Alina Mareș and Aida Petca. Ovarian hyperstimulation syndrome. Obstetrica şi Ginecologia, 2024. URL: https://doi.org/10.26416/obsgin.72.4.2024.10891, doi:10.26416/obsgin.72.4.2024.10891. This article has 0 citations.

22. (alfaraj2023pregnancyoutcomesof pages 2-3): Samaher Alfaraj, Ashwaq A Alharbi, Hind J Aldabal, Yara S Alhabib, and Shihanah AlKhelaiwi. Pregnancy outcomes of assisted reproductive technology (art) cycle complicated by ovarian hyperstimulation syndrome (ohss): case series study. Cureus, Jul 2023. URL: https://doi.org/10.7759/cureus.42303, doi:10.7759/cureus.42303. This article has 6 citations.

23. (NCT05198128 chunk 1): Ahmed Said Ali. Ovarian Hyperstimulation Syndrome Using Calcium Infusion. Al-Azhar University. 2022. ClinicalTrials.gov Identifier: NCT05198128

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