Follicular Fluid Levels of Adrenomedullin 2, Vascular Endothelial Growth Factor and its Soluble Receptors Are Associated with Ovarian Response During ART Cycles

Abstract

Introduction Adrenomedullin 2 (ADM2) and vascular endothelial growth factor (VEGF) affect ovarian function, especially angiogenesis and follicular development. The actions of VEGF can be antagonized by its soluble receptors, soluble Fms-like tyrosine kinase-1 (sFlt-1) and soluble VEGF receptor 2 (sVEGFR-2), as they decrease its free form. In the present study, we evaluated the relationship between follicular fluid (FF) levels of AMD2, VEGF and its soluble receptors, and ICSI outcomes.

Materials and Methods ICSI cycle outcomes were evaluated and FF levels of VEGF, sFlt-1, sVEGFR-2 and ADM2 were determined using ELISA kits.

Results FF levels of ADM2, VEGF, and sVEGFR-2 were significantly higher in non-responders compared to other ovarian response groups (p < 0.05). There were significant correlations between ADM2, VEGF and sVEGFR-2 levels as well as VEGF/sFlt-1 and VEGF/sVEGFR-2 ratios (r = 0.586, 0.482, 0.260, and − 0.366, respectively). Based on the ROC curve, the cutoff value for ADM2 as a non-responder predictor was 348.55 (pg/ml) with a sensitivity of 67.7% and a specificity of 94.6%.

Conclusions For the first time we measured FF ADM2 levels to determine the relationship to VEGF and its soluble receptors. We suggest that ADM2 could be a potential predictive marker for non-responders. Although the exact function of ADM2 in ovarian angiogenesis is not yet understood, our study may shed light on the possible role of ADM2 in folliculogenesis and ovulation.

Zusammenfassung

Einleitung Adrenomedullin 2 (ADM2) und der vaskuläre endotheliale Wachstumsfaktor (VEGF) wirken sich auf die ovarielle Funktion aus, insbesondere auf Angiogenese und Follikelentwicklung. Die Wirkung von VEGF kann durch seine löslichen Rezeptoren (den löslichen Fms-ähnlichen Tyrosinkinase-1 [sFlt-1] und den löslichen VEGF-Rezeptor 2 [sVEGFR-2]) antagonisiert werden, da diese Rezeptoren die freie Form von VEGF reduzieren. In dieser Studie haben wir den Zusammenhang zwischen den Follikelflüssigkeitsspiegeln von AMD2, VEGF und dessen löslichen Rezeptoren und dem Outcome nach ICSI untersucht.

Material und Methoden Das Outcome nach ICSI-Zyklen wurde evaluiert und die Follikelflüssigkeitsspiegel von VEGF, sFlt-1, sVEGFR-2 und ADM2 wurden mithilfe von ELISA Kits bestimmt.

Ergebnisse Die ADM2-, VEGF- und sVEGFR-2-Spiegel in der FF waren signifikant höher in der Gruppe von Frauen ohne ovarielle Reaktion verglichen mit anderen Gruppen mit ovarieller Reaktion (p < 0,05). Signifikante Korrelationen wurden zwischen den ADM2-, VEGF- und sVEGFR-2-Spiegeln sowie den VEGF/sFlt-1- und VEGF/sVEGFR-2-Quotienten festgestellt (r = 0,586, 0,482, 0,260 bzw. − 0,366). Gemäß der ROC-Kurve betrug der Cut-off-Wert für ADM2 als Prädiktor für keine ovarielle Reaktion 348,55 (pg/ml) mit einer Sensitivität von 67,7% und einer Spezifität von 94,6%.

Schlussfolgerungen Wir haben zum ersten Mal die Follikelflüssigkeitsspiegel von ADM2 gemessen und diese Werte mit den Werten von VEGF sowie dessen lösliche Rezeptoren in Beziehung gesetzt. Wir weisen darauf hin, dass ADM2 potenziell ein prädiktiver Marker für das Fehlen einer ovariellen Reaktion sein könnte. Obwohl die genaue Funktion von ADM2 bei der ovariellen Angiogenese noch nicht vollständig geklärt ist, konnte unsere Studie etwas Licht auf auf die möglichen Rollen von ADM2 bei der Follikulogenese und der Ovulation werfen.

Key words

adrenomedullin 2 - vascular endothelial growth factor - sFlt-1 - follicular fluid - ICSI

Schlüsselwörter

Adrenomedullin 2 - vaskulärer endothelialer Wachstumsfaktor - sFlt-1 - Follikelflüssigkeit - ICSI

^* These authors contributed equally and are considered co-first authors.

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