Long‐term mifepristone (RU486) therapy resulting in massive benign endometrial hyperplasia
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Abstract:
Mifepristone (RU486) is a potent antiprogestagen, and at high doses it also acts as an antiglucocorticoid drug. Mifepristone, administered as a single 600 mg dose, is commonly employed to induce medical abortion in conjunction with prostaglandins. The long‐term safety profile of mifepristone, especially at high doses, is less well‐established. Long‐term mifepristone is considered efficacious in treating uterine myomas, endometriosis (25–100 mg/day), and possibly in inoperable meningiomas (200 mg/day), as well as inoperable Cushing's syndrome. Many animal studies document an antiproliferative effect (antioestrogenic), as do some reports in humans. However, there are also data to suggest that, as an antiprogestagen, mifepristone may promote an unopposed oestrogen milieu, and thus have a proliferative effect upon the endometrium. We hereby describe the first reported case of an adolescent female with Cushingoid features and morbid osteoporosis who was treated with mifepristone for its antiglucocorticoid effect (400 mg/day) in an attempt to prevent further bone loss. The patient's striae, weight gain, and buffalo hump markedly improved, and further bone loss was halted. However, with each of the two 6‐month courses of mifepristone (9 months apart) she developed massive simple endometrial hyperplasia and a markedly enlarged uterus. This reversed to normal after cessation of mifepristone treatment. In conclusion, High doses of the antiprogestagen mifepristone over a prolonged period of time may promote an unopposed oestrogen milieu leading to endometrial hyperplasia. Therefore, interval pelvic imaging in women who receive long‐term mifepristone may be prudent.Keywords:
Antiglucocorticoid
Abortifacient
Endometrial hyperplasia
Hormone antagonist
The aim was to examine the effect of mifepristone compound (mifepristone plus anordrin) on estrogen receptors (ER) and progesterone receptors (PR) in early pregnancy decidua. A controlled study was carried out among 60 normal early pregnant volunteers (49 or fewer days) in the Department of Obstetrics and Gynecology at Peking Union Medical Hospital. The concentrations of ER and PR were measured by radioligand and were compared with the control subjects after oral administration of mifepristone or mifepristone compound in different doses. The concentration of PR decreased while that of ER increased significantly in the decidua of all subjects administered mifepristone compound. The authors also found the concentration of EcR in Group 5 (mifepristone 30 mg + AF-53 5 mg) to be the highest among 6 groups. The compound may favor estrogens action on the endometrium. The results indicate that mifepristone compound with AF-53 has a coordinated function and can change the proportion of PR and ER. Hence it can facilitate abortion. The compound dose of mifepristone 30 mg + AF-53 5 mg favors the endometrium recovering. (authors modified)
Decidua
Abortifacient
Medical abortion
Progesterone receptor
Hormone antagonist
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This article reviews the development of mifepristone (RU486) as a female contraceptive drug. Mifepristone is an orally active compound with nearly 40% bioavailability after first pass effect. The steady plasma level of mifepristone ranges from 65 nmol/l with 1 mg/day to 1 micromol/l with 10 mg/day and reaches 2.5 micromol/l, 4.5 micromol/l and 5.4 micromol/l with mifepristone 50 mg, 100 mg and 200 mg daily, respectively, over the treatment period. Inhibition of ovulation may be achieved at serum mifepristone concentration of 232.7 nmol/l. Mifepristone appears to antagonise progesterone at the pituitary level to suppress gonadotropin and steroid hormone secretion rather than to act primarily on the hypothalamus to delay or inhibit ovulation. In fact, the endometrium is most sensitive to mifepristone. Low-dose mifepristone impairs luteal phase endometrial development and receptivity by altering endometrial parakine, cytokine and enzyme activity. Thus, low-dose mifepristone can significantly reduce the rate of conception without inhibiting ovulation. However, further research is needed to standardise the dose and dose-schedule to achieve the desired efficacy of low-dose mifepristone for routine clinical use with minimal or no side-effects.
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A randomized doubbblind study (RU486 versus plaebo) was carried out in order to investigate whether a progesterone antagonist facilitated surgical abortion in the first trimester of pregnancy. The consistency of the cervix changed significantly after RU486 (P < 0.02). We conclude that this effect may facilitate cervical dilatation, making first trimester abortion under local anaesthesia more comfortable and less dangerous.
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Abortifacient
Cervical dilatation
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SUMMARY This article reviews the development of mifepristone (RU486) as a female contraceptive drug. Mifepristone is an orally active compound with nearly 40% bioavailability after first pass effect. The steady plasma level of mifepristone ranges from 65 nmol/l with 1 mg/day to 1 μmol/l with 10 mg/day and reaches 2.5 μmol/l, 4.5 μmol/l and 5.4 μmol/l with mifepristone 50 mg, 100 mg and 200 mg daily, respectively, over the treatment period. Inhibition of ovulation may be achieved at serum mifepristone concentration of 232.7 nmol/l. Mifepristone appears to antagonise progesterone at the pituitary level to suppress gonadotropin and steroid hormone secretion rather than to act primarily on the hypothalamus to delay or inhibit ovulation. In fact, the endometrium is most sensitive to mifepristone. Low‐dose mifepristone impairs luteal phase endometrial development and receptivity by altering endometrial parakine, cytokine and enzyme activity. Thus, low‐dose mifepristone can significantly reduce the rate of conception without inhibiting ovulation. However, further research is needed to standardise the dose and dose‐schedule to achieve the desired efficacy of low‐dose mifepristone for routine clinical use with minimal or no side‐effects.
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Antiglucocorticoid
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Objective: To present a series of cases demonstrating successful reversal of mifepristone effects in women who chose to reverse the medical abortion process. Case Reports: Four of 6 women who took mifepristone were able to carry their pregnancies to term after receiving intramuscular progesterone 200 mg. Discussion: Mifepristone has been available in the US since 2000. By 2008, approximately 25% of abortions prior to 9 weeks were accomplished with mifepristone. Some women who take mifepristone wish to reverse the medical abortion process. Progesterone competes with mifepristone for the progesterone receptor and may reverse the effects of mifepristone. A PubMed literature search from 1996 to May 2012 did not reveal any trials or case studies evaluating the efficacy of progesterone use to reverse the effects of mifepristone. Conclusions: Health care professionals should be aware of the possible use of progesterone to reverse mifepristone in women who have begun the medical abortion process by taking mifepristone and then change their minds.
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Interview with Dr. Michael F. Greene on fatal infections associated with mifepristone-induced abortion. (07:00)Download The Population Council submitted a new drug application to the Food and Drug Administration (FDA) on March 14, 1996, for the progesterone antagonist mifepristone (also known as RU 486) to be used as an abortifacient. The application was based on two studies, involving a total of 4600 women, of the drug's safety and efficacy in the termination of early pregnancies. Four years later, a review article in the Journal1 cited 14 studies of mifepristone with more than 300 patients per study and a total of 26,000 treated women. By the summer of 2000, mifepristone had been used to treat more . . .
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Some women who take mifepristone, a progesterone receptor antagonist, in order to terminate their pregnancies, change their minds and desire to stop the medical abortion process. There are only two articles in the medical literature documenting the reversal of the effects of mifepristone.We present and analyze a series of women who attempted to reverse the effects of mifepristone by taking supplemental progesterone to determine if the reversal of the effects mifepristone with progesterone is possible and safe. Additionally, we compare different progesterone regimens to determine relative efficacies.This is an observational case series of 754 patients who decided to attempt to reverse the medical abortion process after taking mifepristone but before taking the second drug in the protocol, misoprostol. We followed the patients, who were given progesterone in an effort to reverse the effects of mifepristone, and conducted statistical analyses to determine the efficacies of different protocols compared to a control mifepristone embryo survival rate, derived from the literature.Intramuscular progesterone and high dose oral progesterone were the most effective with reversal rates of 64% (P < 0.001) and 68% (P < 0.001), respectively. There was no apparent increased risk of birth defects. Conclusions: The reversal of the effects of mifepristone using progesterone is safe and effective.
Medical abortion
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Abortifacient
Progesterone receptor
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Mifepristone (RU486) is a potent antiprogestagen, and at high doses it also acts as an antiglucocorticoid drug. Mifepristone, administered as a single 600 mg dose, is commonly employed to induce medical abortion in conjunction with prostaglandins. The long‐term safety profile of mifepristone, especially at high doses, is less well‐established. Long‐term mifepristone is considered efficacious in treating uterine myomas, endometriosis (25–100 mg/day), and possibly in inoperable meningiomas (200 mg/day), as well as inoperable Cushing's syndrome. Many animal studies document an antiproliferative effect (antioestrogenic), as do some reports in humans. However, there are also data to suggest that, as an antiprogestagen, mifepristone may promote an unopposed oestrogen milieu, and thus have a proliferative effect upon the endometrium. We hereby describe the first reported case of an adolescent female with Cushingoid features and morbid osteoporosis who was treated with mifepristone for its antiglucocorticoid effect (400 mg/day) in an attempt to prevent further bone loss. The patient's striae, weight gain, and buffalo hump markedly improved, and further bone loss was halted. However, with each of the two 6‐month courses of mifepristone (9 months apart) she developed massive simple endometrial hyperplasia and a markedly enlarged uterus. This reversed to normal after cessation of mifepristone treatment. In conclusion, High doses of the antiprogestagen mifepristone over a prolonged period of time may promote an unopposed oestrogen milieu leading to endometrial hyperplasia. Therefore, interval pelvic imaging in women who receive long‐term mifepristone may be prudent.
Antiglucocorticoid
Abortifacient
Endometrial hyperplasia
Hormone antagonist
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The first clinically available antiprogestin, mifepristone has generated immense interest in the research community since its' discovery in 1980. Mifepristone is a synthetic orally active steroid with potent antiglucocorticoid, antiprogestogen and a weak anti-androgen activity, used primarily for termination of pregnancy. It acts as a competitive receptor antagonist at the progesterone receptor in the presence of progesterone, and acts as a partial agonist in the absence of progesterone. Extensive research has been carried out regarding its' antiprogestogen activity for use in medical abortion. Lately other medical uses of mifepristone are being explored like for induction of labour in late preg- nancy, as oestrogen free oral contraceptive and for treatment of endometriosis, uterine fibroids, ovarian cancer, prostate cancer, meningiomas, Cushing's syndrome and major psychotic depression.
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Progesterone receptor
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Mifepristone is a potent antiglucocorticoid, the administration of which results in a dose-dependent activation of the hypothalamic-pituitary-adrenal axis. However, the net effect of this compound on circulating glucocorticoid activity is not known. We have used a recombinant cell bioassay to study glucocorticoid bioactivity (GBA), measured directly from serum, in 18 women undergoing medical termination of an early pregnancy with 200 mg mifepristone, followed by 0.8 mg misoprostol, a prostaglandin. Increased serum mifepristone was accompanied by an increase in serum cortisol that was insufficient to maintain circulating GBA within the normal (pre-mifepristone) range (34.7–93.8 nm cortisol equivalents); after approximately 43, 46, and 68 h of mifepristone ingestion, the mean serum GBA levels were much lower than the mean pre-mifepristone level (P < 0.0001). At the corresponding times, 16, 13, and 12 women displayed subnormal serum GBA levels (ranges, <15.6–23, <15.6–25.6, and <15.6–32.5 nm cortisol equivalents, respectively). Altogether 11 subjects displayed subnormal serum GBA (range, <15.6–32.5 nm cortisol equivalents) continuously in the presence of high concentrations of mifepristone. Two weeks after mifepristone administration, circulating GBA had returned to normal levels in all subjects. We conclude that 200 mg mifepristone elicits a significant suppression of serum GBA, to one third of the pretreatment value, despite the compensatory increase in the serum cortisol concentration.
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