Dynamics of IGF Signaling During the Ovulatory Peak in Women Undergoing Ovarian Stimulation

Abstract

Context: Insulin-like growth factor (IGF) signaling is known to affect human ovarian follicular function during growth and development. However, the role of the IGF system is unknown during the ovulatory peak, which is characterized by profound changes in granulosa cell (GCs) mitosis and function.

Objective: How is the IGF system expressed and regulated during the midcycle surge in women?

Methods: Follicular fluid (FF) and GCs were collected during the ovulatory peak from 2 specific time points. One sample was obtained before oocyte pickup (OPU): before ovulation trigger (OT) (T = 0 hours) or at 12, 17, or 32 hours after OT, and 1 sample was obtained at OPU 36 hours after OT. Fifty women undergoing ovarian stimulation at a university hospital were included. Gene expression profiles were assessed by microarray analysis of GCs. IGF-related proteins in the FF were assessed by immunoassay or by determination of activity with a proteinase assay.

Results: Gene expression of proteins promoting IGF activity (ie, IGF2, PAPP-A, and IRS1) together with proliferation markers were downregulated on a transcriptional level in GCs after OT, whereas proteins inhibiting the IGF signal (ie, IGFBPs, IGF2, and STC1) were upregulated. STC1 gene expression and protein levels were greatly upregulated after OT with a parallel steep downregulation of PAPP-A proteolytic activity.

Conclusion: These data suggest that downregulation of IGF signaling mediated by increased STC1 expression is instrumental for the sudden cessation in GC proliferation and onset of differentiation during the ovulatory peak.

Keywords: IGF signaling; granulosa cells; human ovarian follicles; ovulation; stanniocalcins.