Поликлиника № 3 Управления Делами Президента РФ, отделение вспомогательных репродуктивных технологий

Effects of cabergoline administration for the prevention of OHSS upon the levels of VEGF, VEGFR-1 and VEGFR-2 in high-risk IVF/ICSI patients

Authors:

S. Fetisova1, I. Korneeva1, T. Saroyan1, L. Krechetova2, T. Ivanets3.
1Research Centre for Obstetrics Gynaecology and Perinatology named after academician V.I. Kulakov, 1st Gynaecology Department, Moscow, Russia C.I.S..
2Research Centre for Obstetrics Gynaecology and Perinatology named after academician V.I. Kulakov, Clinical Immunology Laboratory, Moscow, Russia C.I.S..
3Research Centre for Obstetrics Gynaecology and Perinatology named after academician V.I. Kulakov, Scienific Diagnostics Laboratory, Moscow, Russia C.I.S..

Title:

Effects of cabergoline administration for the prevention of OHSS upon the levels of VEGF, VEGFR-1 and VEGFR-2 in high-risk IVF/ICSI patients

Abstract Text:
Study question

Which effects of cabergoline upon the vascular endothelial growth factor (VEGF) and its receptors (VEGFR-1/VEGFR-2) account for its preventive action in IVF/ICSI patients with high risk of ovarian hyperstimulation syndrome (OHSS)?

Summary answer

Protective effects of cabergoline against OHSS are mediated primarily through the system of VEGF receptors. Cabergoline increases the serum levels of VEGFR-1 and VEGFR-2 from the day of oocyte collection (OC) until the day of embryo transfer (ET), and has no effect upon the VEGF concentrations, which remain steadily elevated.

What is known already

OHSS is a potentially lethal iatrogenic complication of controlled ovarian stimulation. The main pathophysiological mechanism underlying OHSS is a dramatic increase in vascular permeability and angiogenesis, caused by the activation of VEGF system. Recently, an antagonist of D2-receptors with anti-angiogenic activity, cabergoline, started to be successfully used for the prevention of OHSS in high-risk IVF/ICSI patients. However its effects upon the balance between VEGF and its highly specialised and functionally diverse receptors (VEGFR-1/VEGFR-2) in this subgroup of patients remain unknown.

Study design, size, duration

An open, prospective, randomised controlled trial of 168 patients undergoing IVF/ICSI. Inclusion criteria: age<38yrs, basal FSH<12mIU/l, regular menstrual cycle, BMI:18-29kg/m2, ≤2 previous unsuccessful IVF/ICSI cycles. Randomisation to 'cabergoline' or 'no treatment' group was carried out only in a cohort of patients with high risk of OHSS (>15 oocytes retrieved, n=128).

Participants/materials, setting, methods

Sixty-three patients were allocated to receive cabergoline (0.5mg/day for 5 days from the day after OC until the day of ET at the blastocyst stage), and 65 – no treatment. Forty patients comprised a control group. All women received stimulation with rFSH+GnRH antagonists. Serum levels of oestradiol, progesterone, VEGF, VEGFR-1 and VEGFR-2 were assessed on the day of OC and ET.

Main results and the role of chance

Administration of cabergoline in high-risk IVF/ICSI patients from the day of OC until the day of ET resulted in a 19% reduction of absolute risk of early and moderate forms of OHSS. Serum VEGF levels in cabergoline and no treatment group were significantly elevated compared to controls throughout the observation period (OC: 534.8±138.1pg/ml, 529.9±164.1pg/ml and 389.8±182.1pg/ml; ET: 531.3±176.9pg/ml, 595.7±182.9pg/ml and 416.6±180.8pg/ml, p<0.05 for each group vs controls). Cabergoline significantly increased the serum levels of VEGFR-1 and VEGFR-2 from the day of OC to the day of ET (p<0.05), replicating physiological changes in controls. In the no treatment group, no significant changes in the levels of VEGFR-1 and VEGFR-2 were detected. The use of cabergoline did not affect a pregnancy rate per cycle (32.3% vs 36.5%, p>0.05 for cabergoline vs no treatment).

Limitations, reason for caution

This study did not include patients with polycystic ovary syndrome, and therefore, cannot provide answers whether cabergoline has similar effects in this subgroup of patients. Efficacy of cabergoline for the prevention of late and severe forms of OHSS was limited, resulting only in a 5% absolute risk reduction.

Wider implications of the findings

Cabergoline is effective for secondary medical prevention of early non-severe OHSS, and does not affect treatment success. However, careful selection of patients eligible for this strategy is mandatory to avoid undesirable complications. As an additional outcome of this study, we have identified a combination of threshold values for oestradiol and VEGF levels, and the number of retrieved oocytes, which can be used to select a specific subgroup of high-risk IVF/ICSI patients, eligible for the preventive administration of cabergoline.

Study funding/competing interest(s)
Funding by hospital/clinic(s)
This study received institutional support. The authors report no conflict of interest and have nothing to disclose.

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