Dynamic Expression of Endometrial Adhesion G Protein-Coupled Receptors During the Menstrual Cycle and Early Mouse Pregnancy: Modulation by Ovarian Stimulation.

Abstract

Objective: To characterize the expression of adhesion G-protein coupled receptors (ADGR) in the human endometrium and early mouse pregnancy.

Design: An in-silico analysis was performed using a retrospective data set comprised of endometrial samples across normo-ovulatory menstrual cycles. Gene expression was then validated using quantitative reverse transcription polymerase chain reaction (RT-qPCR) and messenger RNA-sequencing (mRNA-seq) in prospectively collected endometrial biopsies in the periovulatory and mid-secretory stages of natural cycles. Gene expression was also investigated under ovarian stimulation conditions using mRNA-seq. Early pregnancy mouse models were used to investigate whether trends of dynamic ADGR expression are also conserved in the mouse.

Subjects: Twenty-four women ages 21-42 years old.

Exposure: Ovulatory menstrual cycle or ovarian stimulation cycle MAIN OUTCOME MEASURES: Gene expression in endometrial biopsies and pregnant mouse uterus.

Results: Fifteen women, ages 21 to 33 years old, were recruited in natural cycles during the proliferative phase (cycle days 10-13; n=4), peri-ovulatory (luteinizing hormone [LH]+12-24 hours; n=6) period and mid-secretory (LH+8 to 9 days; n=5) phase. Nine women ages 31-42 years old undergoing in vitro fertilization (without fresh embryo transfer) or oocyte cryopreservation using a GnRH-antagonist protocol were recruited for the ovarian stimulation cohort in either the peri-ovulatory phase (human chorionic gonadotropin [hCG]+2; n=5) or mid-secretory phase (hCG+9; n=4). The in-silico analysis revealed dynamic expression for many ADGRs across the menstrual cycle. Differential gene expression was also seen in the prospective analysis within the menstrual cycle phases and between natural cycle and ovarian stimulation conditions. Within early mouse pregnancy, expression was also found to be altered across several Adgr subfamilies.

Conclusion: The differential gene expression observed between the proliferative and secretory phases of the menstrual cycle, along with changes in expression seen in ovarian stimulation and early mouse pregnancy suggest that ADGR expression is hormonally regulated by estradiol and progesterone.