Evaluation of endometrial progesterone receptor expression after 12 weeks of exposure to a low-dose vaginal estradiol insert

Abstract

Objective: To evaluate endometrial progesterone receptor (PGR) expression in menopausal women who used vaginal 4-μg and 10-μg estradiol (E2) inserts or placebo.

Methods: REJOICE was a randomized, placebo-controlled trial investigating vaginal E2 inserts in women with moderate to severe dyspareunia due to menopause. In this post hoc analysis, 25 eligible women with endometrial biopsies were randomly selected from each treatment group (4-μg and 10-μg E2 vaginal inserts and placebo). Endometrial biopsy sections were immunostained using an anti-PR (A and B) monoclonal antibody. Cell staining was quantified using an artificial intelligence feature-recognition algorithm. Mean PGR expression levels were analyzed between baseline and week 12.

Results: PGR expression results were available for 22 women in the 4-μg E2 group, and 25 women each for the 10-μg E2 and placebo groups. Similar PGR expression levels were observed at baseline (0.301-0.470 pmol/mg) and after 12 weeks of treatment (0.312-0.432 pmol/mg) for all treatment groups, with no significant differences between baseline and week 12.

Conclusions: No meaningful differences in endometrial PGR expression were observed with the vaginal E2 (4- and 10-μg) inserts at week 12 from baseline, supporting the hypothesis that local exposure to E2 from a low-dose, vaginal insert placed near the vaginal introitus will not be sufficient to upregulate endometrial PGR expression. Coupled with the lack of histologic changes and systemic absorption, our data suggest that these softgel vaginal E2 inserts would not be expected to stimulate endometrial hyperplasia leading to a potential endometrial safety issue in postmenopausal women with moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy. Further study on the endometrial safety of softgel vaginal E2 inserts is under way.

Trial registration: ClinicalTrials.gov NCT02253173.

Conflict of interest statement

Financial disclosure/conflicts of interest: J.A.S. (within the past year, or current) has grant/research support from: AbbVie, Inc., Bayer Healthcare LLC., Endoceutics, Inc., Ipsen, Myovant Sciences, ObsEva SA, TherapeuticsMD, Viveve Medical; has been a consultant/advisory boards of: Allergan, AbbVie, Inc., AMAG Pharmaceuticals, Inc., Bayer HealthCare Pharmaceuticals Inc., Camargo Pharmaceutical Services, LLC, CEEK Enterprises, LLC., Covance Inc., Dare’ Bioscience, Duchesnay USA, Hologic Inc., KaNDy/NeRRe Therapeutics Ltd., Madorra Pty Ltd., Mitsubishi Tanabe Pharma Development America, Inc., Sebela Pharmaceuticals Inc., Shionogi Inc., Sprout2 Inc., TherapeuticsMD; has served on the Speaker's bureaus of: AMAG Pharmaceuticals, Inc., Duchesnay USA, TherapeuticsMD; and is a stockholder (direct purchase) in: Sermonix Pharmaceuticals. J.H.L. consults for Allergan, AMAG, Bayer Healthcare, Daré, Ferring, Lupin, Mitsubishi-Tanabe, Sebela, and TherapeuticsMD and has received research support for clinical trials (paid to UH Cleveland Medical Center) from AbbVie, Allergan, Bayer Healthcare, Femasys, Ferring, and Palatin Technologies. D.F.A. has served as a consultant to AbbVie, Agile Therapeutics, Bayer Healthcare, Endoceutics, Evestra, Exeltis, InnovaGyn, Lupin, Mithra, OvsEva and TherapeuticsMD; and has received research support from Actavis, Bayer Healthcare, Endoceutics, Mithra, Myovant, ObsEva and TherapeuticsMD. He has stock in InnovaGyn and stock options from Agile Therapeutics. B.K. has served as a consultant for TherapeuticsMD and Sermonix. B.B., S.G., and S.M. are employees of TherapeuticsMD with stock/stock options. P.D.C. has nothing to disclose.

Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The North American Menopause Society.

Figures

FIG. 1

Mean expression of the progesterone receptor (PGR) in endometrial biopsies at baseline and week 12 from postmenopausal women receiving E2 vaginal inserts or placebo inserts in the REJOICE study. One sample per woman at each timepoint was assessed with the PGR monoclonal antibody (PgR1294; Agilent, Santa Clara, CA) and analyzed with the Vectra3 imaging and inform software (Akoya Biosciences, Marlborough, MA). aMean difference between week 12 and baseline values and 2-sided t test P values. Kruskal-Wallis P value also shown for the difference between baseline and week 12 values across groups. E2, 17β-estradiol; SE, standard error.

FIG. 2

Representative images of progesterone receptor staining. Cell staining was quantified using a trainable feature-recognition algorithm (Pathology Core and Lab, Baylor College of Medicine, Houston, TX).