What is the definitive cause of Ovarian Hyperstimulation Syndrome (OHSS)?

The Definitive Cause of Ovarian Hyperstimulation Syndrome (OHSS)

The definitive cause of Ovarian Hyperstimulation Syndrome (OHSS) is the administration of human chorionic gonadotropin (hCG) triggering an excessive ovarian response with subsequent increased vascular permeability mediated primarily by vascular endothelial growth factor (VEGF). 1, 2

Pathophysiological Mechanism

• OHSS is an iatrogenic complication of assisted reproduction technology characterized by cystic enlargement of the ovaries and fluid shift from intravascular space to third spaces due to increased capillary permeability 1

• The syndrome is triggered when ovaries primed with follicle-stimulating hormone/luteinizing hormone (FSH/LH) are subsequently exposed to hCG (either exogenous administration or endogenous production in pregnancy) 3, 2

• After hCG administration, there is significant upregulation of VEGF and VEGF receptor-2 (VEGFR-2) mRNA expression in the ovaries, which reaches maximum levels coinciding with peaked vascular permeability 2

• Immunohistochemistry confirms the presence of VEGF and VEGFR-2 proteins in the granulosa-lutein and endothelial cells of the corpus luteum 2

Molecular Mediators

• While multiple vasoactive substances have been implicated in OHSS, VEGF has emerged as the primary mediator responsible for the increased vascular permeability 1, 4

• Other factors that have been implicated but play secondary roles include:

  • Interleukins
  • Tumor necrosis factor-α
  • Endothelin-1
  • Histamine
  • Prostaglandins 1

Risk Factors and Clinical Manifestations

• Underlying thrombophilia increases the risk of severe OHSS 5

• The syndrome manifests as:

  • Ovarian enlargement causing abdominal pain, nausea, and vomiting
  • Ascites from leakage of fluid from follicles and increased capillary permeability
  • Fluid shift from intravascular space to third spaces resulting in intravascular hypovolemia
  • Development of edema, ascites, hydrothorax, and/or hydropericardium 1, 6

• In severe cases, OHSS can lead to:

  • Thrombosis due to hemoconcentration
  • Renal dysfunction
  • Respiratory compromise
  • Electrolyte imbalances 3, 6

Prevention Strategies

• Identification of high-risk patients (those with polycystic ovary syndrome, high follicle counts, or high estradiol levels) 5, 6

• Using the lowest possible dose of gonadotropins to reduce granulosa/luteal cell mass 3

• Withholding gonadotropin stimulation ("coasting") when a large number of follicles (>20) and rising estradiol levels are observed 3

• Using GnRH antagonist protocols rather than agonist protocols, as OHSS is significantly lower with antagonist protocols 1

• Administering dopamine agonists like cabergoline, which inhibit VEGFR-2 phosphorylation and reduce vascular permeability 1, 2

• Cancellation of the cycle and cryopreservation of embryos in high-risk cases 6, 2

Management Approach

• Symptomatic management focused on fluid balance, restoring plasma volume, and improving renal function 3, 4

• Thrombosis prophylaxis with subcutaneous heparin (5000-7500 U/day) beginning on the first day of admission 1

• Aspiration of ascitic fluid to improve patient comfort and potentially remove causative agents 3

• Hospitalization for severe cases with close monitoring of clinical parameters, fluid balance, and laboratory values 1, 6

Understanding that VEGF-mediated increased vascular permeability triggered by hCG is the definitive cause of OHSS has led to more effective prevention strategies and targeted therapeutic approaches in recent years.