New insights in mechanisms for development of ovarian hyperstimulation syndrome.

The ovarian hyperstimulation syndrome (OHSS) is typically an iatrogenic complication of induction ovulation occurring during the luteal phase or early pregnancy. However, the spontaneous form of OHSS is extremely rare and always reported during pregnancy. Several cases have been observed during multiple pregnancies and other cases were associated with hypothyroidism. Moreover, a few mutations of the follicle-stimulation hormone receptor (FSHr) were recently described in spontaneous OHSS and normal levels of human chorionic gonadotrophin (HCG). In these cases, a molecular basis for the pathogenesis of the spontaneous OHSS was identified. These mutations displayed promiscuous sensitivity and activation by both HCG and thyroid stimulating hormone (TSH). The disease always occurs in the presence of either exogenous or endogenous HCG which is thought to play a crucial role in the development of OHSS. The hallmark of OHSS is an increase in capillary permeability resulting in a fluid shift from the intravascular compartment into the third space. It is assumed that HCG induces the release of certain ovarian vasoactive substances or mediators that have potent and direct systemic effects on the vascular system. It was demonstrated that the endothelium, along with the ovary is a primary target for HCG. Of all the different vasoactive components, vascular endothelial growth factor (VEGF) is the principal mediator and the most responsible for increased capillary permeability. It is produced and secreted in the ovary or in the endothelium, and acts through the VEGF receptor-2 or high affinity receptors (KDR and flt 1), respectively. In addition to VEGF HCG may trigger activation of the renin-angiotensin system and kinin-kallikrein system together with releasing of interleukins (6,18), endothelial-cell adhesion molecules, von Willebrand factor, angiogenin and endothelin-1, that also increase vascular permeability.