| In the
absence of a ligand, the progesterone receptor (PR) is associated with different heat
shock proteins (hsp) and is inactive. Association of the receptor with either progesterone
or mifepristone induces conformational changes in the receptor, both of which result in
the dissociation of hsp and the dimerisation of progesterone-receptor or drug
receptor-complexes. Association of the progesterone receptor dimer with the progesterone response elements (PRE) in the promoter regions of progesterone responsive genes activates the transcription of these genes, resulting in an agonist effect on cells and tissues. In the presence of both progesterone and mifepristone, the dimers contain both a progesterone receptor complex and a drug-receptor complex. This dimer (right middle) is transcriptionally inactive., and the effect of progesterone is antagonised. In the absence of progesterone, however, mifepristone can form a complex with Progesterone receptor that dimerizes and is transcriptionally active on some genes, with partial-agonist effects (right bottom) When the progesterone binds to its intracellular receptor, the conformation of the receptor is altered, leading to loss of hsp and the formation of dimers of hormone receptor complexes. The progesterone receptor dimer binds to progesterone response elements (PRE) in the promotor region of progesterone-response genes and increases their rates of transcription causing progesterone effects at the cellular and tissue levels. |
|
| When
mifepristone binds to the progesterone-receptor , the conformation of the receptor changes
in a different way but the same loss of hsp and dimerisation occurs. The mifepristone receptor dimer also binds to PRE elements and activates some genes if progesterone is absent, this is how mifepristone acts as a partial agonist. When both progesterone and mifepristone are present, the dimers that are formed contain a drug receptor complex and a progestin-receptor complex and are transcriptionally inactive, so that the action of progesterone is antagonised at the cellular and tissue level. The short term administration of mifepristone decreases the secretion of lutenizing hormone (LH) in both the follicular and luteal phase of the cycle. Long term administration (3 months) increases the secretion of LH , because mifepristone acts on both the hypothalamus and pituitary and because it has antagonistic agonistic actions. The administration of mifepristone during pregnancy results in the withdrawal of progesterone support to the endometrium, menstrual bleeding and the disruption of placental function (fig.4) |
