Mild hyperandrogenemia in presence/absence of a high-fat, western-style diet alters secretory phase endometrial transcriptome in nonhuman primates.

Abstract Objective To identify novel transcriptomic changes to eutopic endometrium by exposure to chronic mild hypernadrogenemia (T) with/without exposure to an obesogenic western-style diet (WSD). Design 2 by 2 factorial arrangement of treatments. Setting National Primate Research Center Patients/Animals: Rhesus macaque females were chronically exposed to T, and/or consume a WSD from menarche through adulthood. After 4.5 years of treatment Tru-cut endometrial biopsies were obtained at mid-secretory phase (n=6-4/group) and paired-end sequencing of RNA was performed. Several females in T, WSD, and T+WSD cohort developed endometriosis within 6 months of biopsy, a separate analyses was performed contrasting diagnosis of endometriosis Stage 0-II vs Stages IIII DEs) by treatments and endometriosis severity. DEs were then interrogated by Ingenuity Pathway Analyses and PANTHER. Results Total DEs included C vs T, 469; C vs WSD, 525; C vs T+WSD, 549; T vs T+WSD, 1505. The majority of DEs mapped to the Ontology Pathways: Heterotrimeric G-protein signaling pathways Gi alpha and Gs alpha (C vs. T), WNT signaling (C vs. WSD and T vs. T+WSD), and Huntington disease (C vs. T+WSD). 2,171 DE RNAs from eutopic endometrium were altered by presence of Stage III&IV endometriosis lesions. Conclusions The present global transcriptomic analyses demonstrates the greatest magnitude of changes occurred in contrasts of C and T vs. T+WSD, continuing evidence these two insults have a synergistic effect on female physiology. These data also support the concept of prior alterations to the function of eutopic endometrium increasing risk for endometriosis.