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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.

References:

1. Garcia-Velasco JA, Pellicer A. New concepts in the understanding of ovarian hyperstimulation syndrome. 2003. Curr Opin Obstet Gynecol. 15:251-256.

2. Rizk B and Aboulghar M. Classification, pathophysiology and management of hyperstimulation syndrome. In A textbook of in vitro fertilization and assisted reproduction, 2nd ed. Ed. Peter Brinsden. Parthenon, New York. 1999. pages 131-156.

3. Polishuk WZ, Schenker JG. Ovarian hyperstimulation syndrome . 1969. Fertil. Steril. 20:443-7.

4. Schenker JG, Weinstein D. Ovarian hyperstimulation syndrome; a current survey. 1978. Fertil. Steril. 30:255-68.

5. Pride SM, Ho YB, Moon YS. Relationship of gonadotropin-releasing hormone, danazol, and prostaglandin blockade to ovarian enlargement and ascites formation of the ovarian hyperstimulation syndrome. 1986. AJOG 154; 1155-60.

6. Delbaere A, Bergmann PJM, Gervy-decoster C, Staroukine M, Englert Y. Angiotensin II immunoreactivity is elevated in ascites during severe ovarian hyperstimulation syndrome:implications for pathophysiology and clinical management. 1994. Fertil. Streil. 62 (4):731-7.

7. Robertson AL, Khairallah PA. Effects of angiotensin II and some analogues on vascular permeability in the rabbit. 1972. Circ Res. 31:923-31.

8. Navot D, Margalioth EJ, Laufer N. Direct correlation between plasma renin activity and severity of ovarian hypestimulation syndrome. 1987. Fertil. Steril. 48;57-61.

9. Loret de Mola JR, Baumgardner GP, Goldfarb JM. Elevated interleukin-6 levels in the ovarian hyperstimulation syndrome: ovarian immunohistochemical localization of interleukin-6 signal. 1996. Obstet Gynecol 87:581-7.

10. Abramov Y, Schenker JG, Lewin A. Plasma inflammatory cytokines correlate to the ovarian hyperstimulation syndrome. 1996 Human Reprod. 11:1381-86.

11. Krasnow, JJ, Berga SL, Guzick DS, Zeleznik AJ, Yeo K. Vascular permeability factor and vascular endothelial growth factor in ovarian hyperstimulation syndrome: a preliminary report. 1996 Fertil. Steril. 65(3):552-5.

12. Levin ER, Rosen GF, Cassidenti DL, Yee B, Meldrum D, West A, Pedram A.Role of vascular endothelial growth factor in ovarian hyperstimulation syndrome. 1998 . J Clin Invest. 102:1978-1985.

13. Gomez R, Simon C, Remohi J, Pellicer A. Vascular endothelial growth factor receptor-2 activation induces vascular permeability in hyperstimulated rats, and this effect is prevented by receptor blockade. Endocrinology 143:4339-4348.
 

 

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