Selective progesterone receptor modulators (SPRMs): progesterone receptor action, mode of action on the endometrium and treatment options in gynecological therapies

Abstract

Introduction: The progesterone receptor plays an essential role in uterine physiology and reproduction. Selective progesterone receptor modulators (SPRMs) have emerged as a valuable treatment option for hormone dependent conditions like uterine fibroids, which have a major impact on women's quality of life. SPRMs offer potential for longer term medical treatment and thereby patients may avoid surgical intervention.

Areas covered: The authors have reviewed the functional role of the progesterone receptor and its isoforms and their molecular mechanisms of action via genomic and non-genomic pathways. The current knowledge of the interaction of the PR and different SPRMs tested in clinical trials has been reviewed. The authors focused on pharmacological effects of selected SPRMs on the endometrium, their anti-proliferative action, and their suppression of bleeding. Potential underlying molecular mechanisms and the specific histological changes in the endometrium induced by SPRMs (PAEC; Progesterone receptor modulator Associated Endometrial Changes) have been discussed. The clinical potential of this compound class including its impact on quality of life has been covered.

Expert opinion: Clinical studies indicate SPRMs hold promise for treatment of benign gynecological complaints (fibroids, heavy menstrual bleeding; HMB). There however remains a knowledge gap concerning mechanism of action.

Keywords: Cofactors; HMB; PAEC; endometrium; selective progesterone modulator.

Figure 1.

Immunolocalisation of ERα and PR in full thickness sections of human endometrium. Images shown from four samples of uterine tissue recovered during the early (ES) or mid (MS) secretory phases of the cycle: each section represents the full thickness of the uterine wall with the lumen at the top and myometrium at the bottom. Sections were co-stained for ERα (red) and PR (green) using standard protocols [32] for clarity the images recorded in the different channels (red, green) are shown side-by-side rather than overlaid. Note that during the ES there is intense immunopositive staining for both ERα and PR-A in the glandular epithelium in both the functional (arrows) and basal (white asterisks) layers. During the MS immunoexpression in the epithelium is down-regulated but expression of PR in stromal fibroblasts is maintained (green asterisks). Full color available online.

Figure 2.

Structure of common SPRMs. Chemical structures of selective progesterone receptor modulators (SPRMs) in current clinical use or which have been in clinical development.

Figure 3.

Image of progesterone receptor (PR) immuno-reactivity in human endometrium after administration of a selective PR modulator (SPRM). Note intense positive (brown) immunostaining in the glandular epithelium (g) and virtual absence of immuno-reactivity in the stroma (s). Image kindly provided by Professor Alistair Williams, University of Edinburgh. Full color available online.