| In early
pregnancy, RU-486 interupts pregnancy by opposing the action of progesterone at several
sites in the uterus. in normal pregnancy the trophoblast (the future placenta) secretes
human choronic gonadotrophin (hCG) which maintains the corpus luteum. Progesterone
secreted by the corpus luteum supports pregnancy by maintaining a secretory endometrium,
inhibiting contratility of uterine muscle and firming the cervix and inhibiting dilation.
When progesterone is inhibited by mifepristone the endometrim erodes, and the embryo is
detached and expelled along with the endometrial tissue. Evacuation of the uterus is also
favoured by mifepristone in mifepristone in softening and dilating the cervix. When RU-486 is administered in early luteal phase as a single dose of 5 to 200 mg it induces uterine bleeding 40-57 hours after ingestion. In mid-Luteal phase mifepristone (orally administered) in doses of 25, 50, 800mg daily for 3 days, in nearly all healthy woman studied. Further bleeding at the time of expected menstruation occurs in two thirds of the woman tested. In these woman who bled twice the 1st occurred in the presence of elevated progesterone levels, indicating that RU-486 blocks the action of progesterone at the level of the endometrium. In late luteal phase, administration of mifepristone 100mg daily for 4 days resulted in bleeding within 1-3 days of treatment. The luteal phase of the treatment cycle was shortened and the following follicular phase of the next cycle is lengthened. To summarise the administration of mifepristone to normal woman in early and mid luteal phases of the menstrual cycle induces profound changes in the endometrium and menstrual bleeding occurs within 72 hours. |
|
The
characterisations of these endometrial changes are:
All of these changes are consistent with the withdrawal of progesteroneš. In postmenopausal woman receiving estrogens alone, mifepristone effects on the endometrium are similar to those of progesterone, suggesting it also have some progesterone agonist properties in certain circumstances. Mifepristone and progesterone interact differently with the receptor and produce different conformational changes in the receptor. Progesterone acts within the cell by occupying the progesterone receptor in the nucleus. The hormone modifies the receptor’s shape enabling it to bind to chromatin, leading to gene transcription and protein synthesis. RU-486 antagonises theses effect by occupying the receptor without stimulating gene transcription. It may block transcription by failing to induce the change in receptor shape so it won’t bind to chromatin or it may change its shape so that the chromatin binds but it may prevent binding by critical transcription factors (fig.3) |
