Plasma Levels of Soluble Vascular Endothelial Growth Factor Receptor-1 (sVEGFR-1) Play a Key Role in the Onset of Early (E-) and Late (L-) Ovarian Hyperstimulation Syndrome (OHSS)

Abstract

OHSS is associated with ovarian stimulation in infertile women. E-OHSS is the consequence of hCG administration; L-OHSS is induced by trophoblastic hCG. Both develop in women carrying characteristics still not defined, and have an auto-regulation never explored before. VEGF is a system of ligands and receptors associated with increased vascular permeability (VP) in OHSS. Alternative mRNA splicing of its receptor 1, produces sVEGFR1 a natural inhibitor which reduces the availability of free (f-)-VEGF. We aimed to analyze the dynamics of the VEGF system in E- and L-OHSS in order to understand who develops OHSS, and the mechanism(s) determining its life span. Moreover, the only proposed VEGF sequester, (α2Macroglobulin (α2M), was also measured. A prospective study of women at risk (multicystic antral follicles in basal conditions and >20 oocytes retrieved) who did and did not develop OHSS, and patients without risk. Additionally, oocyte donation (OD) was compared to IVF-ICSI pregnancies, to determine the origin of the molecular players of L-OHSS E-OHSS: Non-pregnant patients were included. Group 1 (n=11) had no risk of OHSS; Group 2 (n=18) were women at risk who did not develop OHSS; Group 3 (n=8) did develop severe OHSS with culdocentesis due to ascites. Evaluation including blood parameters and pelvic ultrasound to evaluate ovarian size and ascites, was performed the day of ovum pick-up (day 0), 3, 6 10 and 14 days later. Serum and/or plasma was obtained. L-OHSS: Single pregnancies were studied weekly (4th to 12th) classified in: Women who did not develop (group 4, n=8); and did develop (group 5, n=4) severe OHSS requiring culdocentesis. An additional control group (n=4) was formed of single clinical pregnancies after OD and followed similar to groups 4 and 5, grouped in a single group named IVF-ICSI for comparison.Total VEGF, f-VEGF and sVEGFR1 were measured in plasma by ELISA . Serum E2 and P4 were measured by enzyme immunoassay, (α2M was measured employing nephelometry. Statistical methods were applied with the SPSS program; a p<0.05 was statistically significant. The figure shows the dynamics of sVEGFR1 secretion in E- and L-OHSS as well as comparison between IVF-ICSI and OD. The difference in the availability of sVEGFR1 determined the appearance of severe OHSS. Women in group 3 secreted very low levels as compared to groups 1 and 2. The placenta is an important source of sVEGFR1, but OD pregnancies are deficient in this regard. The differences in sVEGFR-1 determined the levels of f-VEGF in the luteal phase (E-OHSS) and first trimester of pregnancy (L-OHSS), whereas (α2M had no effect. Despite significantly (p<0.05) higher f-VEGF levels in OD, these patients did not develop OHSS.Analysis of serum E2 and P4 in the luteal phase showed levels compatible with a functional corpus luteum in group 3. Rather, an increase in sVEGFR1 may be the initiator of OHSS demise. In E- and L-OHSS, the ability to secrete sVEGFR1 reducing the availability of f-VEGF is the determinant factor which induces the severity and limits in time OHSS. f-VEGF increases VP in the ovaries, since OD patients do not develop OHSS.