Figure 7.

Schematic diagram to illustrate differential genomic (nuclear) and nongenomic (extranuclear, cytoplasmic) actions of progestogens and endogenous steroid hormones. The two progestins, MPA and norethindrone, were chosen to illustrate the concept of differential actions compared with each other and progesterone. In genomic actions, all progestogens bind to the PR and act as agonists. MPA is a partial to full agonist for the GR and AR but has no significant activity via the MR or ER. However, norethindrone is a partial to full agonist for the AR but has no significant activity via the GR, MR, or ER. Progesterone is a weak agonist for the GR and AR, has no significant activity via the ER, and is a full antagonist for the MR. The two best-characterized genomic mechanisms for steroid receptors are illustrated. The first is transactivation by steroid receptor dimers binding directly to SREs in the promoters of target genes, followed by recruitment of coactivators and increased transcription. The second is transrepression via tethering of a steroid receptor monomer to other positively acting transcription factors, followed by recruitment of a corepressor and inhibition of transcription. Other complexes and higher-order effects on chromatin structure as discussed in the text are not depicted for simplicity. The depicted nongenomic or cytoplasmic actions include activation of various cytoplasmic targets by the classical nuclear steroid receptors or by membrane steroid receptors. Progesterone is a full agonist for the mPR, whereas MPA and norethindrone have no significant activity via mPR. Note that cytoplasmic actions can also lead to genomic actions by targeting of nuclear proteins such as transcription factors, cofactors, and chromatin proteins or even steroid receptors. Also depicted is the cross talk between the classical PR and other plasma membrane receptors (R) such as the epidermal growth factor receptor, as discussed in the text. Note that actions of progesterone as a weak GR or AR agonist are not depicted. ALD, aldosterone; CORT, cortisol; E₂, estradiol; mER, membrane ER; NET, norethindrone; PROG, progesterone; SR, steroid receptor; TEST, testosterone; TF, transcription factor.