Ovarian hyperstimulation syndrome inhibition by targeting VEGF, COX-2 and Calcium pathways: a preclinical randomized study

Kitsou, Chrysoula; Kosmas, Ioannis; Lazaros, Leandros; Hatzi, Elissavet; Euaggelou, Aggelos; Mynbaev, Ospan A.; Tournaye, Herman; Πράπας, Νικόλαος; Prapas, Ioannis; Zikopoulos, Konstantinos; Galani, Vasiliki; Georgiou, Ioannis

doi:10.3109/09513590.2014.910191

Cited by 12 publications

(17 citation statements)

References 23 publications

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“…Prior researches illustrated that VEGF is the main mediator in the pathogenesis of OHSS [1,2,3,4] . Infertility investigator introduced oral cabergoline as VEGF receptor antagonist [17,18] and calcium infusion [35,36,37,38,39] as VEGF lowering agent, so they targeting VEGF at different points of OHSS pathogenesis cascade and comparing both drugs against placebo as well as versus each other and reporting varying degree of success of both agents. This trial tested the interaction of adding oral cabergoline as VEGF receptor antagonist with calcium infusion as VEGF lowering drug and found a significant lowering effect of this combination on overall OHSS incidence [overall OHSS 87.2%) 110/) in CI+ versus 1816.3%) 110/) in CI-with ∆pp = -9.1% at 95% CI of (-0.49, -17.8), P = 0.036] as well non significant lowering effect on moderate (p = 0.3) and severe (p = 0.3) OHSS.…”

Section: Discussionmentioning

confidence: 99%

Calcium infusion plus or minus cabergoline for prevention of ovarian hyperstimulation syndrome: Randomized double-blind placebo-controlled trial

Sharafeldeen

2018

Evidence Based Women's Health Journal

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Aim: To evaluate the interaction of adding oral cabergoline (OC) to calcium infusion as a preventive modality for ovarian hyperstimulation syndrome (OHSS) in risky women undergoing controlled ovarian hyperstimulation (COH) in context of in-vitro fertilization (IVF) / intracytoplasmic sperm injection (ICSI). Patients and Methods: This prospective, double-blind, randomized, placebo-controlled trial was conducted at Benha IVF center of Obstetrics and Gynecology Department of Benha University and Nour Al Hayah Fertility Center Between January 2015 and February 2016. 220 risky women for OHSS undergoing ICSI were included, they were randomized to 110 women received once daily OC for eight days, starting at HCG triggering and infusion of calcium gluconate 10 ml 10% in 200 ml 0.9% saline daily for 4 days beginning at ovum pick up (OPU), coined as calcium infusion plus group (CI+) and 110 women received only calcium infusion in the same fashion as in CI+ coined as calcium infusion minus group (CI-). The primary outcome was the overall incidence of OHSS while the secondary issues were OHSS types and grades as well as other ICSI outcomes. Results: The incidence of overall OHSS was significantly lower in calcium infusion plus oral cabergoline (CI+) group compared to calcium infusion alone (CI-) group [8/110(7.2%) in CI+ versus 18/110 (16.3%) in CI-with difference in proportion percentage point (∆PP)=-9.1%, 95% CI: -0.49, -17.4; P = 0.036]. Despite the incidence of moderate and severe OHSS was lower in CI+ than in CI-, this difference didn't reach the significance level (2.7% vs 5.4%; p = 0.3) and (0.9% versus 2.7%; ), respectively. The other COH and ICSI outcomes didn't show any statistically significant differences. Conclusion: Adding oral cabergoline to calcium infusion is effective than calcium infusion alone in the reduction of overall OHSS incidence as well as its severity at comparable pregnancy outcomes.

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Section: Discussionmentioning

confidence: 99%

Calcium infusion plus or minus cabergoline for prevention of ovarian hyperstimulation syndrome: Randomized double-blind placebo-controlled trial

Sharafeldeen

2018

Evidence Based Women's Health Journal

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“…The 3rd group (rec-FSH + hCG + mTOR inhibitor + calcium inhibitor, at half dose compared to previous studies [1,2] Medication were stored and used according to the manufacturers' instructions. All doses were recommended doses for efficacy in humans, but extrapolated to animal weight.…”

Section: Interventionsmentioning

confidence: 99%

“…Evans Blue dye combines with the albumin fraction and is thus distributed in the intravascular space [4,5]. The procedure was previously described [2]. In brief, rats were anesthetized with ketamine hydrochloride (Sigma Aldrich, Chemie Gmbh, Steinheim, Germany) and kept in thermal blanket to avoid hypothermia.…”

Section: Vascular Permeability Testmentioning

confidence: 99%

“…In specific, the inhibition of mTOR using Everolimus led to ovarian weight and progesterone reduction [1], while the inhibition of calcium pathway using Verapamil had a profound effect on vascular permeability [2]. Everolimus and Verapamil may have a synergistic action, taking into account the increase of Everolimus concentration with the co-administration of Verapamil as well as the doubling of Verapamil concentration after the administration of Everolimus [3].…”

Section: Introductionmentioning

confidence: 98%

“…Various doses and days of administration were selected according to previous studies [1,2]. Apart from Everolimus plus Verapamil (mTOR inhibitor and calcium inhibitor) at half dose as well as at half days (the last two days of treatment), we also tested Heparin (anticoagulant), Montelukast (leukotriene inhibitor) and a GnRH antagonist for their effectiveness in the prevention of OHSS.…”

Section: Introductionmentioning

confidence: 99%

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The combination of Everolimus with Verapamil reduces ovarian weight and vascular permeability on ovarian hyperstimulation syndrome: a preclinical experimental randomized controlled study

Kitsou

Kosmas

Lazaros

et al. 2016

Gynecological Endocrinology

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The efficacy of pathways inhibition and the combined effect of Everolimus (mTOR inhibitor) and Verapamil (CYP3A inhibitor) in ovarian hyperstimulation syndrome (OHSS) need to be tested. Therefore, the impact of a leucotriene receptor antagonist, an anticoagulant, a GnRH antagonist as well as Everolimus plus Verapamil (at various doses and days of administration) on an OHSS rat model was tested. Sixty three female Wistar rats were randomly divided into seven groups. The control group received saline, while the OHSS group received rec-FSH for four consecutive days. The other five groups received rec-FSH for four days and Montelukast daily, Heparin daily, GnRH antagonist daily, Everolimus plus Verapamil in the last two days (half days group) and Everolimus plus Verapamil (half dose group) daily, respectively. All groups received also hCG at the fifth day. Significantly reduced ovarian weight was observed in the Everolimus plus Verapamil groups (half days and half-dose groups) and the Montelukast group compared to the OHSS group (p = 0.001 and p = 0.001, respectively). The vascular permeability was significantly reduced in the Everolimus plus Verapamil group (half dose group) and the GnRH antagonist group compared to the OHSS group (p< 0.001 and p = 0.011, respectively). However, estradiol and progesterone levels did not differ significantly between the groups. Studying the inhibition of different pathways, we concluded that the co-administration of Everolimus and Verapamil (at half dose) is beneficial for reducing ovarian weight and vascular permeability in an OHSS animal model.

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Assisted Reproductive Technique Complications in Pregnancy

Kosmas

Tatsi²,

Sifakis

et al. 2016

Management and Therapy of Early Pregnancy Complications

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Ovarian hyperstimulation syndrome inhibition by targeting VEGF, COX-2 and Calcium pathways: a preclinical randomized study

Abstract: Studying the different check points of the VEGF pathway, we conclude that targeting calcium pathways could be beneficial for the vascular permeability control in an OHSS animal model.

Cited by 12 publications

References 23 publications

Calcium infusion plus or minus cabergoline for prevention of ovarian hyperstimulation syndrome: Randomized double-blind placebo-controlled trial

Calcium infusion plus or minus cabergoline for prevention of ovarian hyperstimulation syndrome: Randomized double-blind placebo-controlled trial

The combination of Everolimus with Verapamil reduces ovarian weight and vascular permeability on ovarian hyperstimulation syndrome: a preclinical experimental randomized controlled study

Assisted Reproductive Technique Complications in Pregnancy

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