ABSTRACT
CONTEXT: Prokineticin 1 (PROK1) quantification in global follicular fluid (FF) has been recently reported as a predictive biomarker of in vitro fertilization (IVF) outcome. It is now necessary to evaluate its clinical usefulness in individual follicles. OBJECTIVES: To evaluate the clinical value of PROK1 secretion in individual FF to predict oocyte competence. To determine the impact of follicular size, oocyte maturity, and gonadotropin treatments on PROK1 secretion. DESIGN AND SETTING: Prospective cohort study from May 2015 to May 2017 at the University Hospital of Grenoble. PATIENTS: A total of 69 infertile couples underwent IVF. INTERVENTION(S): Collection of 298 individual FF from 44 women undergoing IVF; 52 individual cumulus cell (CC) samples and 15 CC primary cultures from 25 women undergoing IVF-intracytoplasmic sperm injection (ICSI). MAIN OUTCOME MEASURE(S): Oocyte competence was defined as the ability to sustain embryo development to the blastocyst stage. Follicular size was measured by 2D-sonography. PROK1 concentration was quantified by ELISA assay. RESULTS: PROK1 concentration was correlated to follicular size (r = 0.85, P = 2.2 × 10-16). Normalized PROK1 concentration in FF was predictive of subsequent oocyte competence (AUROC curve = 0.76 [95% CI, 0.69-0.83]; P = 1.7 × 10-9), irrespectively of day-2 embryo morphokinetic parameters. The expression and secretion of PROK1 were increased in FF and CC of mature oocytes (P < 0.01). Follicle Stimulating Hormone and hCG up-regulated PROK1 secretion in CC primary cultures (P < 0.01; P < 0.05), probably through the cAMP pathway (P < 0.01). CONCLUSIONS: PROK1 quantification in individual FF could constitute a new predictive biomarker of oocyte competence in addition with embryo morphokinetic parameters. TRIAL REGISTRATION NUMBER: none.
Subject(s)
Biomarkers/analysis , Embryonic Development , Follicular Fluid/chemistry , Gastrointestinal Hormones/analysis , Oocytes/physiology , Vascular Endothelial Growth Factor, Endocrine-Gland-Derived/analysis , Biomarkers/metabolism , Cells, Cultured , Cohort Studies , Embryonic Development/drug effects , Embryonic Development/genetics , Embryonic Development/physiology , Female , Fertilization in Vitro , Follicular Fluid/metabolism , France , Gastrointestinal Hormones/genetics , Gastrointestinal Hormones/metabolism , Gene Expression/drug effects , Hormones/pharmacology , Humans , Oocyte Retrieval/standards , Oocytes/cytology , Oogenesis/drug effects , Oogenesis/genetics , Oogenesis/physiology , Pregnancy , Pregnancy Rate , Prognosis , Prospective Studies , Quality Control , Sperm Injections, Intracytoplasmic , Treatment Outcome , Vascular Endothelial Growth Factor, Endocrine-Gland-Derived/genetics , Vascular Endothelial Growth Factor, Endocrine-Gland-Derived/metabolismABSTRACT
CONTEXT: Prokineticin 1 (PROK1), also called endocrine gland-derived vascular endothelial growth factor, is a well-established regulator of endometrial receptivity and placental development. However, its clinical usefulness as a noninvasive predictive biomarker of embryo implantation is yet to be validated. OBJECTIVE: The main objective of this article was to determine the relationship between PROK1 levels in the follicular fluid (FF) and fertilization culture media (FCM) and the reproductive outcome in patients who received a first conventional in vitro fertilization-embryo transfer. The secondary objective was to characterize the expression of PROK1 and its receptors (PROKRs) in the human follicular microenvironment. DESIGN AND SETTING: We conducted a prospective study between January 2013 and June 2015 at the University Hospital of Grenoble. PATIENTS: A total of 135 infertile in vitro fertilization patients and 10 women undergoing ovarian tissue cryopreservation were included. INTERVENTIONS: The PROK1 concentration was measured by ELISA in FF and FCM collected on the day of oocyte retrieval and the day of the oocyte denudation step, respectively. Follicular expression of the PROK1/PROKR system was determined by immunohistochemistry, RT-quantitative PCR, and ELISA. MAIN OUTCOME MEASURE: Assessment of the clinical pregnancy rates was the main outcome. RESULTS: FF and FCM PROK1 levels were significantly higher in the embryo implantation group (P < .001) and were predictive of subsequent embryo implantation (area under the receiver operating characteristic curve, 0.91 [95% confidence interval, 0.81-1.00], P = .001; and 0.88 [0.72-1.00], P = .001, respectively). FF and FCM PROK1 levels remain similar irrespective of the embryo morphokinetic parameters (P = .71 and P = .83, respectively). The PROK1/PROKR system is expressed during human folliculogenesis. CONCLUSIONS: PROK1 levels in FF and FCM could constitute new predictive noninvasive markers of successful embryo implantation in conventional in vitro fertilization-embryo transfer.
