Features of Ovarian Hyper-Stimulation Syndrome (OHSS)
Ovarian hyperstimulation syndrome (OHSS) may complicate gonadotropin therapy for IUI or ART. Ovarian enlargement, ascites, pleural/pericardial effusions, electrolyte imbalances, coagulopathies occur and may be life-threatening. Increased vascular permeability leading to hemoconcentration is central. HCG is the primary stimulus for the syndrome in most cases. OHSS can occur without exogenous gonadotropin stimulation in several situations including (a) gonadotroph adenoma secreting FSH and LH, (b) molar pregnancy with increased HCG secretion, (c) PCOS patients that are pregnant and over-respond to endogenous gonadotropins, and (d) patients with primary hypothyroidism where the high levels of TSH stimulate the FSH receptor (1). Several classification schemes are proposed. Rizk and Aboulghar (2) simplified classification with two categories, moderate and severe OHSS. Moderate OHSS has discomfort, pain, nausea, abdominal distention, ascites and enlarged ovaries , but normal hemotologic and biologic profiles. Severe OHSS Grade A has dyspnea, oliguria, nausea, vomiting, diarrhea, abdominal pain, distention of the abdomen or hydrothorax, enlarged ovaries, marked ascites and normal biochemical profiles. Severe OHSS grade B has the above with massive tension ascites, markedly enlarged ovaries, severe dyspnea , marked oliguria, increased hematocrit, increased creatinine and liver dysfunction. Grade C OHSS is complicated by respiratory distress syndrome, renal shutdown, or venous thrombosis.
Capillary leakage leads to decreased intravascular volume, oliguria, possible renal dysfunction and electrolyte disruption. Decreased blood volume may lead to hyperviscosity and thrombosis. Supraphysiologic levels of estradiol may induce hepatic procoagulants leading to thrombosis. Several potential mediators of OHSS have been studied, though the precise cause is unknown. Elevated estradiol is not the cause. High doses of estradiol do not induce OHSS in rats (3). Prostaglandins, i.e. PGI-2, are involved with ovulation and may lead to follicle wall permeability. Inhibitors of prostaglandins alter fluid shifts in OHSS (4). In contrast, indomethacin was found not to alter the course of OHSS in another study (5). Thus, prostaglandins may not be major factors. The rennin-angiotensin system is present within the ovary. It is elevated in the ascites of women with OHSS (6). Angiotensin II may increase vascular permeability (7). A direct correlation between plasma renin activity and the severity of OHSS was reported (8).
Ovulation involves a cytokine cascade. Several cytokines have been studied. IL-6 is a mediator of increased vascular permeability and is elevated in OHSS (9). Others found IL-1, IL-6, and TNF increased in OHSS (10). VEGF, a potent mediator of vascular permeability/angiogenesis is produced in the ovary and elevated in OHSS (11). VEGF antibody blocks endothelial cell permeability induced by follicular fluid (12). In a mouse model investigators using a synthetic blocker of VEGF receptor-2 phosphorylation were able to reverse the effects of HCG induced permeability (13). Thus many mediators play a role in OHSS. Hopefully better treatments will come from better understanding of these factors.
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factor receptor-2 activation induces vascular permeability in
hyperstimulated rats, and this effect is prevented by receptor blockade.