Mechanism of Action of Mifepristone in Pregnancy Prevention and Termination
Mifepristone terminates pregnancy primarily by binding to progesterone receptors and blocking progesterone's effects, which causes decidual breakdown and detachment of the embryo, not by making the endometrium inhospitable to a zygote before implantation. 1, 2
Primary Mechanism: Decidual Breakdown After Implantation
The FDA-approved mechanism centers on antiprogestational effects that result in termination of established pregnancy through several coordinated actions 2:
- Mifepristone binds to cytosolic progesterone receptors (both PR-A and PR-B subtypes), rendering the receptor complex inactive and preventing gene transcription 1, 3
- This binding causes decidual breakdown and deterioration of the uterine lining that is already supporting an implanted embryo 1, 4
- Progesterone normally maintains the endometrium in a secretory state necessary to sustain pregnancy; blocking this effect leads to detachment of the embryo 4
The drug was originally discovered during research on glucocorticoid receptor ligands but was found to have more potent antiprogesterone effects, leading to its development specifically for pregnancy termination 1, 3.
Clinical Efficacy by Gestational Age
Mifepristone is most effective for pregnancy termination up to 7 weeks gestation, with declining efficacy as gestational age increases 3, 5, 6:
- At ≤49 days gestation: 92% complete termination rate 7
- At 50-56 days: 83% complete termination rate 7
- At 57-63 days: 77% complete termination rate 7
The American College of Obstetricians and Gynecologists recommends mifepristone (typically 600 mg) followed by misoprostol (400 mcg) as the established regimen for first-trimester medical abortion 5, 7.
Endometrial Effects: A Secondary Mechanism
While the question suggests mifepristone works by making the endometrium "inhospitable," this represents only a potential contraceptive mechanism at very low doses, not the primary abortifacient mechanism 4, 8:
- Very low daily doses (0.5 mg) or weekly doses (2.5-5 mg) can alter endometrial receptivity markers without inhibiting ovulation 8
- These doses cause profound alterations in endometrial morphology that may prevent implantation 4, 8
- However, the endometrium is more sensitive to antiprogestin effects than the ovulatory process 8
This contraceptive potential remains investigational and is not the mechanism by which mifepristone terminates established pregnancies 9, 8.
Additional Mechanisms Supporting Pregnancy Termination
Beyond decidual breakdown, mifepristone exerts several complementary effects 3, 4:
- Inhibition of the pituitary luteinizing hormone surge, resulting in anovulation and amenorrhea 3
- Direct antiproliferative and pro-apoptotic effects on reproductive tissues 3
- Endometrial changes that reduce bleeding when used in other contexts 3
Important Clinical Caveats
The FDA mandates pregnancy exclusion before initiating mifepristone for any non-abortion indication, as the antiprogestational effects will terminate pregnancy 2:
- Pregnancy must be excluded before treatment initiation and if treatment is interrupted for >14 days 2
- Non-hormonal contraception must be used during treatment and for one month after stopping 2
- For high-risk patients requiring pregnancy termination, management should occur in experienced centers with emergency support available 3, 5, 6
Mifepristone's mechanism is fundamentally different from emergency contraception (which prevents fertilization or implantation) because it acts after implantation has occurred to cause detachment of an established pregnancy.