Ulipristal Acetate Interferes With Actin Remodeling Induced by 17β-Estradiol and Progesterone in Human Endometrial Stromal Cells

Abstract

Ulipristal acetate (UPA) is a selective progesterone receptor modulator (SPRM) used for emergency contraception and for the medical management of symptomatic uterine fibroids (UF). Treatment with UPA turns in amenorrhea and UF volume reduction. Treatment with UPA is associated with the frequent development of benign, transitory endometrial changes known as SPRM-associated endometrial changes (PAECs). Why PAECs develop and their biological or cellular basis is unknown. Sex steroids, including estrogen and progesterone, are established modulators of the actin cytoskeleton in various cells, including endometrial cells. This explains several morphological and functional changes in endometrial cells. We thus hypothesized that UPA may alter the appearance of the endometrium by interfering with the actions of 17β-estradiol (E2) or progesterone (P4) on actin dynamics. We isolated and cultured human endometrial stromal cells (ESC) from endometrial biopsies from healthy fertile women. Treatment with E2 or P4 stimulated visible actin rearrangements with actin remodeling toward the membrane. Activation through phosphorylation of the actin regulatory proteins, Moesin, and focal adhesion kinase (FAK), hacked actin remodeling induced by E2 and P4. Membrane re-localization of Paxillin and Vinculin were also induced by E2 and P4, showing the formation of focal adhesion complexes. All these E2 and P4 actions were inhibited by co-treatment with UPA, which was otherwise inactive if given alone. The cytoskeletal changes induced by E2 and P4 turned into increased motility of ESC, and UPA again blocked the actions E2 and P4. In conclusion, we find that UPA interferes with the cytoskeletal actions of E2 and P4 in ESC. This finding helps understanding the mode of actions of SPRMs in the endometrium and may be relevant for other potential clinical applications of UPA.

Phase III long‐term study to evaluate the efficacy and safety of ulipristal acetate in Japanese patients with uterine fibroids

“…Consistent with studies in European and Japanese women 17 , 22 and the known mechanism of action of UPA, 23 , 24 the nonphysiological changes that occurred at the endometrium during treatment with SPRMs were temporary and benign. Mean endometrial thickness was not different from baseline levels by the end of the study.…”

Estrogen influences the transzonal projection assembly of cumulus‐oocyte complexes through G protein‐coupled estrogen receptor during goat follicle development

“…On the other hand, both of them are directly involved in regulating oocyte meiosis, because TZP contraction would lead to failure of cGMP transport from somatic cells to oocytes. Studies have shown that estrogen is a regulator of the actin skeleton in various cells, and estrogen regulates actin cytoskeletal reorganization via different molecular mechanisms and signaling pathways (Giretti et al, 2014;Kramar et al, 2009;Shortrede et al, 2018;Wang et al, 2020).…”

“…On the other hand, both of them are directly involved in regulating oocyte meiosis, because TZP contraction would lead to failure of cGMP transport from somatic cells to oocytes. Studies have shown that estrogen is a regulator of the actin skeleton in various cells, and estrogen regulates actin cytoskeletal reorganization via different molecular mechanisms and signaling pathways (Giretti et al, 2014; Kramar et al, 2009; Shortrede et al, 2018; Wang et al, 2020). ERK1/2 is a serine/threonine protein kinase involved in the regulation of a variety of biological processes, including cell adhesion, cell cycle progression, cell migration, cell survival, differentiation, metabolism, and proliferation (Roskoski, 2012).…”

Ulipristal Acetate (UPA) in Emergency Contraception: The Mechanism of Action, Toxicity and Perspectives

“…UPA interferes with estradiol and progesterone actions in ESC by decreasing actin cytoskeleton rearrangement, focal adhesion formation, and reducing FAK and Moesin phosphorylation/activation. This leads to an alteration of cell morphology and to the inhibition of cell motility 58 . The above discussion lets us understand that the main MOA of ellaOne ® is its anti-implantation effect on the endometrium, whenever it is taken in the menstrual cycle.…”