In the uterus, coordinated myometrial cell contraction is not triggered by neural activation; instead, myometrial cells work together as a contractile syncytium through cell-to-cell gap junction connections permitting the intercellular sharing of small molecules, which in turn facilitates activation of the actin-myosin contractile apparatus and coordinated uterine contraction. In myometrial cells, connexin 43 (Cx43) is the main gap junction protein. Cx43 permits the passage of small hydrophilic molecules (ATP) and ions (calcium) cell to cell. Estradiol increases Cx43 synthesis in human myometrial cells.1 Progesterone decreases Cx43 synthesis effectively isolating myometrial cells, reducing cell-to-cell sharing of chemicals that stimulate contraction, blocking coordinated uterine contraction.2 Progesterone suppression of Cx43 synthesis helps to prevent premature uterine contraction during pregnancy. At term, decreases in progesterone levels result in an increase in Cx43 synthesis, facilitating the onset of effective labor. In myometrial cells, antiprogestins, including mifepristone, increase the number of gap junction connections, facilitating a coordinated contractile signal in response to misoprostol or oxytocin.3,4
It takes time for antiprogestins to stimulate myometrial cell production of Cx43. In the rat myometrium the administration of mifepristone results in a 2.5-fold increase of Cx43 mRNA transcripts within 9 hours and a 5.6-fold increase in 24 hours.3 Hence, most mifepristone treatment protocols involve administering mifepristone and waiting 24 to 48 hours before administering an agent that stimulates myometrial contraction, such as misoprostol. Antiprogestins also increase the sensitivity of myometrial cells to oxytocin stimulation of uterine contractions by increasing Cx43 concentration.4
Progesterone also regulates other important biological processes in the cervix, decidua, placenta, and cervix. Antiprogestins can facilitate cervical ripening and disrupt decidual function, interfering with the attachment of pregnancy tissue.5 In the cervix, antiprogestins increase matrix metalloproteinase expression, disrupting collagen organization, decreasing cervical tensile strength and leading to cervical ripening.6
Pharmacology of mifepristone
Mifepristone is an antiprogestin and antiglucocorticoid with high-affinity binding to both the progesterone and glucocorticoid receptors (FIGURE 1). The phenylaminodimethyl group at C-11 of mifepristone changes the positional equilibrium of helix 12 of the progesterone receptor, reducing the ability of the receptor to bind required co-activators, limiting receptor binding to DNA, resulting in an antiprogesterone effect.7 At the low, single-dose used for treatment of miscarriage and fetal demise (200 mg one dose), mifepristone is an antiprogestin. At the high, daily dose used for the treatment of hyperglycemia caused by Cushing disease (≥ 300 mg daily), mifepristone is also an antiglucocorticoid.
FIGURE The chemical structure of progesterone and the antiprogestin, mifepristone. When mifepristone binds to the progesterone receptor, the phenylaminodimethyl group at C-11 reduces the ability of the mifepristone-progesterone receptor complex to bind co-activators necessary for the initiation of DNA transcription, creating an antiprogestin effect.
Although mifepristone is a powerful antiglucocorticoid, in patients with an intact hypothalamic-pituitary-adrenal axis, mifepristone does not cause adrenal insufficiency. In people with an intact hypothalamic-pituitary-adrenal axis, daily administration of mifepristone (≥ 200 mg) for 7 days or longer results in an increase in pituitary secretion of ACTH and adrenal secretion of cortisol, largely overcoming the antiglucocorticoid action of mifepristone.8-10 This compensatory increase in ACTH and cortisol is not possible in patients who have had a hypophysectomy or bilateral adrenalectomy or have adrenal suppression due to long-term treatment with high doses of glucocorticoids. Mifepristone is contraindicated for patients with these conditions because it may cause glucocorticoid insufficiency by blocking glucocorticoid receptors.
The terminal half-life of mifepristone is 18 hours.11 Following oral administration of a single dose of mifepristone 200 mg the peak circulating concentration is reached in 90 minutes. Mifepristone is metabolized by CYP3A4 and is also a strong inhibitor of CYP3A4. Contraindications to the use of mifepristone include adrenal failure, porphyria, hemorrhagic diseases, anticoagulation, an IUD in the uterus, ectopic pregnancy, long-term glucocorticoid administration, and an undiagnosed adnexal mass.
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