F&S science · 2021
The selective progesterone receptor modulator, telapristone acetate, is a mixed antagonist/agonist in the human and mouse endometrium and inhibits pregnancy in mice.
СтатьяПоддержка исследования: вне правительства СШАПоддержка NIH: внешняя программаНазвание и аннотация: Перевод пока не подготовлен
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McAvey Beth, Kuokkanen Satu, Zhu Liyin, Pollard Jeffrey W
Аннотация
OBJECTIVE: To investigate the effect of the selective progesterone receptor modulator, telapristone acetate (CDB-4124), on endometrial biology and reproductive outcomes. Ovariectomized and hormone-treated CD1 female mice, CD1 female mice with xenotransplants of reconstructed human endometrial tissue, mated wildtype female mice, and cultured human endometrial stromal cells (hESCs) were treated with CDB-4124, followed by the assessment of endometrial cell deoxyribonucleic acid (DNA) proliferation, stromal decidual response, and embryo implantation.
DESIGN: Experimental study.
SETTING: Academic research laboratory.
PATIENTS: Healthy volunteer women from the community were recruited for endometrial biopsies.
ANIMALS: CD1 out-bred mice (Charles River Laboratories) and nude mice, NU/J (Jackson Laboratories, Bar Harbor, ME).
INTERVENTION: Treatment of mice and hESCs with CDB-4124.
MAIN OUTCOME MEASURE: The effect of CDB-4124 on endometrial cell morphology and DNA synthesis, decidual response, and mouse embryo implantation.
RESULTS: CDB-4124 inhibited estradiol-induced epithelial DNA synthesis in the mouse uterus and xenotransplanted human endometrium. This antiproliferative effect was less than that of progesterone (P4) and was observed when CDB-4124 was administered alone or concomitantly with P4. In the uterine epithelium, CDB-4124 acted as a P4 agonist and partial antagonist. In contrast, CDB-4124 acted as a complete P4 antagonist in the uterine stroma, where it blocked P4's action to induce a decidual response in the pseudopregnant mouse uterus and wildtype mouse uterus after copulation. In mated female mice, CDB-4124 impaired embryo implantation. Similarly, CDB-4124 inhibited the morphological and biochemical transformations of hESCs to decidual cells in vitro.
CONCLUSION: CDB-4124 exerts mixed P4 antagonistic/agonistic effects in the human and mouse endometrium, which result in failed embryo implantation because of the absence of stromal decidualization.
DESIGN: Experimental study.
SETTING: Academic research laboratory.
PATIENTS: Healthy volunteer women from the community were recruited for endometrial biopsies.
ANIMALS: CD1 out-bred mice (Charles River Laboratories) and nude mice, NU/J (Jackson Laboratories, Bar Harbor, ME).
INTERVENTION: Treatment of mice and hESCs with CDB-4124.
MAIN OUTCOME MEASURE: The effect of CDB-4124 on endometrial cell morphology and DNA synthesis, decidual response, and mouse embryo implantation.
RESULTS: CDB-4124 inhibited estradiol-induced epithelial DNA synthesis in the mouse uterus and xenotransplanted human endometrium. This antiproliferative effect was less than that of progesterone (P4) and was observed when CDB-4124 was administered alone or concomitantly with P4. In the uterine epithelium, CDB-4124 acted as a P4 agonist and partial antagonist. In contrast, CDB-4124 acted as a complete P4 antagonist in the uterine stroma, where it blocked P4's action to induce a decidual response in the pseudopregnant mouse uterus and wildtype mouse uterus after copulation. In mated female mice, CDB-4124 impaired embryo implantation. Similarly, CDB-4124 inhibited the morphological and biochemical transformations of hESCs to decidual cells in vitro.
CONCLUSION: CDB-4124 exerts mixed P4 antagonistic/agonistic effects in the human and mouse endometrium, which result in failed embryo implantation because of the absence of stromal decidualization.