The transcriptional activity of progestins used in contraception and menopausal hormone therapy via progesterone receptor A is dependent on the density of the receptor

Studies directly comparing the efficacies and potencies of multiple progestins used in contraception and menopausal hormone therapy (MHT) in parallel via human progesterone receptor isoform A (PR-A) in the same model system are limited, and how these parameters are influenced by the density of PR-A are unclear. This is surprising as it is known that the expression levels of PR-A vary in different tissues and diseases. We thus determined for the first time the relative efficacies and potencies for transactivation of the natural PR ligand, progesterone (P4), the PR-specific agonist promegestone (R5020), and selected progestins from all four generations in parallel via different densities of PR-A overexpressed in the MDA-MB-231 breast cancer cell line. Comparative dose-response analysis showed that P4, R5020, the 1st generation progestins medroxyprogesterone acetate and norethisterone, 2nd generation progestin le-vonorgestrel, 3rd generation progestin gestodene, as well as 4th generation progestins nesterone, nomegestrol acetate and drospirenone display differential agonist efficacies and potencies via PR-A. Moreover, we showed that the agonist efficacies and potencies of the progestins via PR-A were modu-lated in a density-and progestin-specific manner. Our finding that the potencies of the progestins via PR-A, at all densities, do not exceed reported progestin serum concentrations in women, suggest that these progestins are likely to elicit similar effects in vivo. We are the first to report that P4 and the selected progestins display similar agonist activity for transrepression via PR-A, and that the density of PR-A enhances the transrepression activity of some, but not all progestogens. Collectively, our findings pro-vide proof of concept that the effects of the selected progestins via PR-A is progestin-specific and dependent on the density of the receptor, suggesting differential progestin responses in women using these progestins in contraception and MHT.(c) 2022 Elsevier Inc. All rights reserved.

Automated summary

This study reveals the differential agonist efficacies and potencies of various progestins via different densities of PR-A in the same model system. It also suggests that the effects of these progestins are specific to each progestin and dependent on the density of the receptor. These findings have important implications for contraception and menopausal hormone therapy.