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

Figures & data

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.

Table 1. Non-genomic signaling pathways reported to be triggered by progesterone.

Involved signaling pathways
SRC/ERK/MAPK pathway Delayed P-dependent neuroprotection mediated by Src-ERK signaling Cyclin D1 gene induction by PR activation of the Src/MAPK pathway Rapid activation of Src/Erk1/2 and PI3K/Akt pathways in breast cancer and endometrial stromal cells via crosstalk between PR and ERα/β	Boonyaratanakornkit et al.,[58] Cai et al.,[59] Ballare et al.,[60] Mani et al. [7]
PI3K/Akt/NFκB pathway Stimulation mPR by P activates the PI3K/Akt/NFκB pathway resulting in (1) inactivation of FOXO transcriptional activity and (2) downregulation of miR-29c which triggers KLF4	Vares et al. [61]
MEK1/2 and PKA Activation of macrophages by P via mPR causes pro-inflammatory shift in mRNA expression profile and significant upregulation of cyclooxygenase 2, Il1B, and TNF and downregulation of mPRα MEK1/2 and PKA are involved in mPR signaling	Lu et al.,[62] Mani et al. [7]
PKC Rapid increase in basal PKC activity in VMN by P	Balasubramanian et al. [63]
Calcium and calmodulin kinase II P-activation of CaMKII basal activity in VMN	Balasubramanian et al. [64]
PKG PgRMC1 shown to mediate rapid progestin actions in various tissues (including brain) by potential activation of PKG	Bashour et al. [65]

PKA: Protein kinase A; PKC: protein kinase C; VMN: ventromedial nucleus; PKG: protein kinase G; PgRMC1: progesterone receptor membrane component 1.

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.

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