Transcriptome landscapes induced by estetrol, estradiol, and ethinylestradiol in primary human endometriotic stromal cells.

Abstract

Objective: To compare the transcriptomes induced by estrogens used in combined oral contraceptives (COCs): estetrol (E4), ethinylestradiol (EE), and estradiol (E2) in human primary endometriotic stromal cells.

Design: Endometriotic stromal cells were cultured in the presence of E4 (10^-6 mol/L), E2 (10^-8 mol/L) or EE (10^-9 mol/L) for 24 hours. Transcriptomes induced by E4 were compared with those induced by E2 and EE.

Subjects: Endometriotic stromal cells were obtained from patients with ovarian endometriomas.

Main outcome measures: Transcriptomes were examined using RNA sequencing analysis, and messenger RNA levels were measured using reverse transcription-quantitative polymerase chain reaction.

Results: Estetrol treatment resulted in 114 differentially expressed genes compared with the control (|log2fold change| >0.2). The number was higher than those differentially expressed between E4 and E2 (82 genes) and between E4 and EE (75 genes). Of the differentially expressed genes between E4 and the control, 79% (90 genes) changed in the same manner as in EE and E2. In contrast, 21% (24 genes) of the genes changed in an E4-preferential manner.

Conclusion: The present study elucidated that although E4 induces the expression of specific unique genes in endometriotic stromal cells distinct from those regulated by other estrogens, the overall gene expression profile is largely analogous to that induced by other estrogens. When differences in progestin are not considered, it is suggested that the COC containing E4 exhibits effects on endometriosis comparable with those of other COCs.