Premature formation of nucleolar channel systems indicates advanced endometrial maturation following controlled ovarian hyperstimulation

Abstract

To evaluate the temporal appearance of nucleolar channel systems (NCSs) in the human secretory endometrium in natural cycles (Nat) and following ovarian hyperstimulation with (OH+S) and without (OH) vaginal progesterone (P4) (Endometrin; Ferring Pharmaceuticals). Is there a shift in NCS formation following controlled ovarian hyperstimulation (COH)? Prospective two-cohort study. Consecutive endometrial biopsies were obtained from healthy, oocyte donors on cycle days (CD) 16, 20 and 26 (cohort I, n=7), or CDs 14, 22 and 24 (cohort II, n=8) following random assignment to a Nat, OH or OH+S group, with at least one ‘wash-out’ cycle between groups. NCS prevalence in the nuclei of endometrial epithelial cells (EECs) was quantified (#NCSs/#EECs x 100, %) using indirect immunofluorescence with an antibody directed against certain nuclear pore complex proteins, that are major constituents of NCSs. Estradiol and P4 levels were measured on the day of each biopsy. Nat group exhibited peak NCS prevalence on CD20 (53%; interquartile range [IQR] 28.5-55.8), rapid decline on CD22, 24 and 26, and no NCSs on CD14 and 16. In contrast, after OH and OH+S, NCS prevalence was high already on CD16 (40.4%; IQR 22.6-53.4 and 35.6%; IQR 26.4-44.5, respectively; p=0.001, Mann-Whitney). No other significant differences were noted between the groups on any of the other five cycle days (p>0.1). In these healthy oocyte donors, NCS prevalence occurs when expected in the mid-luteal phase of natural cycles. In contrast, premature appearance of NCSs and hence maturation of the endometrium is observed following COH. This is the first study of this kind that is based on consecutive endometrial biopsies within the same cycle and that reports all-or-none data. Our observation of advanced endometrial maturation following COH may contribute to the reduced implantation success rates in fresh vs. frozen IVF-ET cycles.