Mifepristone: a potential clinical agent based on its anti-progesterone and anti-glucocorticoid properties.

Nowadays, unwanted pregnancy is a major globe tragedy for millions of women, associated with significant direct and indirect costs, no matter for individuals or society. The progesterone receptor antagonist steroid, mifepristone has been widely and effectively using throughout the world for medical abortion, but to a lesser extent for emergency contraception. In this review, we hope to explore the role of mifepristone as a contraceptive, particularly for emergency contraception. Studies of mifepristone have also been expanding to the fields of endometriosis and uterine fibroids. Furthermore, this initially considered reproductive medicine has been investigated in some psychotic diseases and various disorders of hypercortisolism, because of its glucocorticoid receptor antagonism. Mifepristone was approved suitable for patients with hyperglycemia secondary to Cushing's syndrome by the United States Food and Drug Administration (FDA) in 2012. The aim of this article is to review published reports on the anti-progesterone and anti-glucocorticoid properties of mifepristone as a clinical agent. There is a new insight into systematically describing and evaluating the potential efficiency of mifepristone administrated in the field of endocrine and neuroendocrine, not only in obstetrics and gynecology.

Centchroman: is unsupervised long-term use warranted? Case report.

OBJECTIVES: Centchroman (Ormeloxifene) is a synthetic non-steroidal compound used as an oral and a post-coital contraceptive. It is currently under trial for treatment of breast cancer and postmenopausal osteoporosis. Centchroman has been reported to induce only minimal side effects and no hormonal imbalance. CASE: A young woman who used centchroman for a long time in an unsupervised fashion presented with menorrhagia, which was controlled with norethisterone. Her massively enlarged uterus showed extensive decidual changes in a hyperplastic endometrium, and diffuse microglandular cervical hyperplasia. CONCLUSIONS: The case suggests a prominent oestrogenic effect of centchroman on the uterus. This could be a significant adverse effect related to prolonged therapy. Lengthy intake of centchroman requires medical surveillance and long-term studies are needed.

Mifepristone: where do we come from and where are we going? Clinical development over a quarter of a century.

Administration of mifepristone followed by the prostaglandin, misoprostol, has been used successfully in the medical termination of pregnancy for over 25 years, and the method is registered in 35 countries. Single doses of mifepristone are also effective as an emergency postcoital contraceptive. Mifepristone administered for 3 months or longer to women with uterine leiomyomas, is associated with a reduction in pain and bleeding with improvement in quality of life and decrease in fibroid size. Mifepristone is also effective in decreasing pain in women with endometriosis. In both these conditions, serum estradiol levels are in the range of those in the early follicular phase. A daily dose of at least 2 mg mifepristone blocks ovulation. In contrast, weekly administration of 25 or 50 mg does not consistently block ovulation but has contraceptive potential by delaying endometrial development. Mifepristone in a dose of 200 mg, administered 48 h after the Luteinizing Hormone (LH) surge, also acts as a contraceptive, but this strategy is not practical for widespread use. Administration of mifepristone for 4-6 months or longer may lead to endometrial thickening. Endometrial histology reveals cystic glandular dilation together with admixed estrogen (mitotic) and progestin (secretory) epithelial effects. This histological pattern does not represent endometrial hyperplasia.

Immediate pre-ovulatory administration of 30 mg ulipristal acetate significantly delays follicular rupture.

BACKGROUND: Current methods of hormonal emergency contraception (EC) are ineffective in preventing follicular rupture when administered in the advanced pre-ovulatory phase. This study was designed to determine the capacity of ulipristal acetate (UPA), a selective progesterone receptor modulator developed for EC, to block follicular rupture when administered with a follicle of >or=18 mm. METHODS: This was a double-blind, crossover, randomized, placebo-controlled study. Thirty-five women contributed with UPA (30 mg. oral) and a placebo cycle. Serial blood sampling for luteinizing hormone (LH), estradiol and progesterone measurements and follicular monitoring by ultrasound were performed before and for 5 days following treatment. Follicular rupture inhibition was assessed in the overall study population and in subgroups of women stratified by when treatment was administered in relation to LH levels (before the onset of the LH surge, after the onset of the surge but before the LH peak or after the LH peak). RESULTS: Follicular rupture failed to occur for at least 5 days following UPA administration in 20/34 cycles [59%; 95% confidence interval (CI) (40.7-75.4%)], whereas rupture took place in all cycles within 5 days of placebo intake. When UPA was administered before the onset of the LH surge, or after the onset but before the LH peak, follicle rupture had not occurred within 5 days in 8/8 (100%) and 11/14 [78.6%; 95% CI (49.2-95.3)] cycles, respectively. In contrast, when UPA was given after the LH peak, follicle rupture inhibition was only observed in 1/12 [8.3%; 95% CI (0.2-38.5)] cycles. CONCLUSIONS: This study demonstrates that UPA can significantly delay follicular rupture when given immediately before ovulation. This new generation EC compound could possibly prevent pregnancy when administered in the advanced follicular phase, even if LH levels have already begun to rise, a time when levonorgestrel EC is no longer effective in inhibiting ovulation.

Anticoncepción hormonal de emergencia y embarazo ectópico: caso clínico / Emergency contraception and ectopic pregnancy: clinical case

El riesgo de embarazo ectópico después de anticoncepción de emergencia es un hecho conocido y con el aumento de la demanda por este método, es esperable un mayor número de casos en el futuro. Se presenta un caso de embarazo ectópico después del fracaso de la anticoncepción de emergencia con levonorgestrel.

The risk of ectopic pregnancy after emergency contraception is known and with the increased use of this treatment, we might expect more cases in the future. One case of ectopic pregnancy after failure of emergency contraception with levonorgestrel is presented.

Pharmacological properties of mifepristone: toxicology and safety in animal and human studies.

Roussel Uclaf in partnership with the INSERM unit of Prof. E.E. Baulieu first discovered mifepristone (RU486) as part of a large research program on steroidal compounds with antihormone properties. Exhibiting a strong affinity to the progesterone and the glucocorticoid receptors, mifepristone exerted competitive antagonism to these hormones both in in vitro and in animal experiments. Due to its antiprogesterone activity, it was proposed that mifepristone be used for the termination of early human pregnancy. Mifepristone, at a dose of 600 mg initially used alone, was then used with a subsequent low dose of prostaglandin that led to a success rate of 95% as a medical method for early termination of pregnancy (TOP). Its use was extended to other indications, such as cervical dilatation prior to surgical TOP in the first trimester, therapeutic TOP for medical reasons beyond the first trimester, and for labor induction in case of fetal death in utero. The efficacy and safety of this treatment has been confirmed based on its use for over a decade, with close adherence to the approved recommendations. This paper describes the safety studies conducted in animals as well as the safety follow-up and side effects reported with use of the compound in various indications either approved or unapproved. The rationale for warnings and contraindications for use of the product are also explained. At lower doses, the molecule has proven promising for contraceptive purposes with few reported side effects. However, development of the product for this indication would require long-term studies. Although political and philosophical obstacles have delayed research, the use of mifepristone for other potential indications in gynecology or oncology should be investigated.

Ectopic gestation following emergency contraceptive pill administration.

Emergency contraceptive pill prescription following rape is common. We report a case of ectopic gestation after emergency contraceptive pill failure and review the literature on this rare complication. A 26-year-old woman with a normal menstrual period 2 weeks before was administered an emergency contraceptive pill 8 hours after a single sexual assault. The assault was her only sexual activity before and after the emergency contraceptive pill use. Forty-six days following the assault, the patient presented with a right ampullary tubal pregnancy of 59 days gestation and underwent emergent surgery for ectopic gestation. To prevent a delay in the diagnosis of ectopic pregnancy, we recommend that providers and the package insert advise women, that ectopic gestation can occur with emergency contraceptive pill failure.

Experimental study on relationship between exogenous estrogen and breast cancer risk.

OBJECTIVE: To investigate the relationship between exogenous estrogen and breast cancer risk. METHODS: Female rats were randomly divided into three groups, namely diethylstilbestrol (DES), norethindrone compositae (CoNET) and control group. The histological structure and ultrastructural changes of mammae were observed. The levels of sexual hormones in serum were determined and the AgNOR counts, DNA contents and steroid receptor contents in mammary epithelium were also detected. RESULTS: In DES group, the level of progesterone (10.38 ng/ml) was obviously lower than that in the control group (13.37 ng/ml); the incidence of hyperplasia of mammary gland (73.33%) was significantly higher than that in the control group (7.69%); and the degree of hyperplasia was obviously more serious than that in the control group. Moreover, there were 13.33% of rats with atypical hyperplasia in DES group. The DNA contents, AgNOR counts and estrogen receptor (ER) positive rate were markedly higher in DES group (95.60, 2.43 and 71.71% respectively) than in the control group (83.07, 1.88 and 40% respectively). However, in CoNET group, there were no obvious influences on ER, AgNOR and DNA in mammary epithelium. CONCLUSIONS: Exogenous estrogen (DES) could affect the levels of sexual hormones in serum, accelerate the DNA duplication, increase the AgNOR counts and ER contents, and induce atypical hyperplasia and ultrastructural changes of mammary gland, hence becoming a latent risk factor of breast cancer. However, the results failed to suggest that the contraceptive, CoNET, could increase the risk of breast cancer.

RU-486=Preguntas y respuestas / RU-486 Question and answer

Los fármacos con antiprogestina constituyen un nuevo método prometedor para el control de la natalidad. El RU-486, también conocido con el nombre de mifepristone, es el primer fármaco con antiprogestina disponible en el mercado. Hasta ahora se ha aprobado en Francia y China como alternativa no quirúrgica para terminar los embarazos en su etapa inicial. Siguen investigándose las distintas aplicaciones anticonceptivas del RU-486, que también parece tener varios otros usos terapéuticos. El RU-486 y otros fármacos parecidos pueden contribuir a eliminar las complicaciones relacionadas con las actuales técnicas quirúrgicas del aborto. Estos fármacos son potencialmente menos costosos y más aceptables para muchas mujeres que el aborto quirúrgico. Hoy en día, los expertos en medicina recomiendan usar el RU-486 dentro de un período de tres semanas después de producido el atraso menstrual y administrarlo junto con otro fármaco, la prostaglandina, la cual aumenta mucho su efectividad. En vista de que a veces se presentan problemas de hemorragias y abortos incompletos, el RU-486 debe tomarse bajo supervisión médica. El RU-486 podría reducir enormemente las defunciones por abortos practicados en condiciones deficientes en los países en desarrollo. Pero como este fármaco se ha convertido en objeto de considerables controversias, es probable que en muchos países su disponibilidad dependa de factores políticos

[Postcoital contraception]. / Postcoïtale anticonceptie.

PIP: Some form of postcoital contraception for protection against unwanted pregnancy is indispensable today especially in cases of rape, failed mechanical contraception, or 1st sexual contact without contraception. A tabletform of postcoital contraceptive would be acceptable if 100% certainty is assured and it doesn't involve adverse effects. Postcoitally administered high-dose estrogens proved effective in Macaca mulatta. Diethylstilbestrol in variable dosages with or without ethinylestradiol was used in various studies and with variable results. Pregnancy rates depended on time of coitus in cycle, contraceptive dosage, and time of administration after coitus (within 72 hours). Conjugated estrogens and various progestagens or combinations of both have been tried with variable success. Another form of postcoital contraception is IUD insertion within 7 days following unprotected coitus. Advantages of this method are the time factors and absence of adverse effects of hormonal contraceptives. Postcoital hormonal contraceptives cause changes in the endometrium which prevent blastocyst implantation. They alter tubal function affecting zygote movement towards the uterus. They have an antiovulatory effect and may be luteolytic. Estrogens have more severe side effects than progestagens. Nausea, vomiting, mastodynia, fluid retention, and vaginal bleeding can result from estrogens. Progestagens can cause irregular bleeding. Combination of both can cause menstrual irregularity. Postcoital hormonal contraceptives are contraindicated in heart and liver diseases, thrombosis, and pregnancy (teratogenic and carcinogenic effects on offspring). Pregnancy despite postcoital contraception results in extrauterine pregnancy in 10% of patients. The most important reservations in evaluating publications on this subject are: 1) lack of control group; 2) estimation of pregnancy probability is not reliable because of study population used; 3) patient fertility cannot be ascertained; and 4) reliability of information provided by patient. Conclusion from literature studies is that postcoital hormonal contraception is of value but effectiveness is not proven. More research is needed and indications are that other less radical drugs may be found in near future.^ieng

[Chromosomal analysis of baboons and their mothers, following application to mothers of potentially post-ovulation fertility-inhibiting steroids (author's transl)]. / Chromosomenanalytische Untersuchungen der nach der Anwendung potentieller postovulatorisch-fertilitätshemmender Steroide geborenen Paviane und deren Mütter.

One single does of 0.4 mg of steroid compounds Levonorgestrel (13-ethyl-17alpha-ethinyl-17beta-hydroxy-gon-4-en-3-on) or STS 557 (17alpha-cyanomethyl-17beta-hydroxy-13beta-methylgona-4.9-dien-3-on) was administered to each of six baboon mothers, right after mating. No indication whatsoever to possible mutagenic action of the compounds applied under the given experimental conditions were recordable from the bone-marrow cells of the mothers nor from the lymphocytes of peripheral blood of their newborns. Chromosomal aberrations recorded from this species were within normal limits.