Selective progesterone receptor modulators in reproductive medicine: pharmacology, clinical efficacy and safety  Philippe Bouchard, M.D., Nathalie Chabbert-Buffet, M.D., Ph.D., Bart C.J.M. Fauser, M.D., Ph.D.  Fertility and Sterility  Volume 96, Issue 5, Pages 1175-1189 (November 2011) DOI: 10.1016/j.fertnstert.2011.08.021 Copyright © 2011 American Society for Reproductive Medicine Terms and Conditions

Figure 1 Mechanism of action of progesterone and selective progesterone receptor modulators (SPRMs). (A) After entering the cytoplasm of the target cell, progesterone binds to the progesterone receptor (PR) which causes a conformational change in the PR, resulting in the dissociation of chaperone proteins, PR dimerization, and binding of the progesterone–PR protein complex to progesterone response elements in the promoters of target genes. Two major different isoforms of PR (PR-A and PR-B) exert different gene selective biological activities. This allows the progesterone–PR protein complex to interact with coactivators, facilitating communication with the basal transcription apparatus and ultimately leading to transcription of the target gene (12, 13). Steroid hormone receptors, including the PR, can also activate nongenomic signaling pathways in the absence of steroid hormone (14, 15). (B) Interaction of SPRMs with the progesterone receptor isoforms (PR-A/B) induces a conformational change in the PR, which allows a more potent recruitment of corepressors (such as nuclear receptor corepressor (NCoR) and silencing mediator of retinoid and thyroid hormone receptor [SMRT]) to the PR than that induced by progesterone. However, under these conditions the PR ligand-binding domain can also interact with the coactivators SRC-1 and AIB1 (29). As the precise conformational change induced in the PR, and thus the balance of interaction with coactivators and corepressors depends upon the identity of the individual SPRM molecule to which the PR is bound, each SPRM has a different and unique molecular signature (7, 28–30). Furthermore, the precise activity of each SPRM will vary by tissue, depending on the relative levels of coactivators and corepressors in each cellular environment. Fertility and Sterility 2011 96, 1175-1189DOI: (10.1016/j.fertnstert.2011.08.021) Copyright © 2011 American Society for Reproductive Medicine Terms and Conditions

Figure 2 Chemical structures of progesterone, norethindrone, and selected selective progesterone receptor modulators. Fertility and Sterility 2011 96, 1175-1189DOI: (10.1016/j.fertnstert.2011.08.021) Copyright © 2011 American Society for Reproductive Medicine Terms and Conditions