小剂量米非司酮和左炔诺孕酮用于紧急避孕的临床研究

目的：以左炔诺孕酮为参比制剂,探讨10mg米非司酮用于紧急避孕的临床效果。副反应及可接受性。方法：采用随机对照性的试验方法,征集100例单次无保护性交72小时内来院就诊的要求紧急避孕的妇女,随机分配到观察组（n=50）和对照组（n=50）,观察组单次口服10mg米非司酮,对照组口服左炔诺孕酮0．75mg,12小时后再服左炔诺孕酮0．75mg,服药后嘱两组对象按时随访直至月经复潮。并观察其避孕效果,副反应,对月经的影响及药物的可接受性。结果：采用Dixon方法计算。两组对象各有1例妊娠,观察组避孕效果达81．19％,对照组为81．06％,统计学上无明显差并,两组副反应轻,无任何不良反应发生。结论：小剂量米非司酮用于紧急避孕与左炔诺孕酮是同样有效的。     

小剂量米非司酮用于紧急避孕200例的临床观察

目的 比较米非司酮25mg和10mg用于紧急避孕的有效性、副反应、对月经周期的影响。方法 采用双盲随机比较试验方法,共接纳合格妇女200例1次无防护性交72小时内随机进入第一组和第二组,第一组一次性口服米非司酮25mg和安慰剂1片;第二组一次性口服米非司酮10mg。随访至月经来潮,了解避孕效果、副反应、月经周期的变化。结果两组分别有2例和1例妊娠,失败率分别为2％和1％,避孕有效率分别为82.21％和90.18％,p>0.05,无统计学意义;副反应很轻微,发生率很低;服药时间对月经周期有影响;两种药量对月经周期没影响。结论 小剂量米非司酮25mg和10mg用于紧急避孕同样有效,并且效果良好。     

Comparison of Yuzpe regimen,danazol, and mifepristone (RU486) in oral postcoital contraception.

OBJECTIVE--To compare the effectiveness and acceptability of three regimens of postcoital contraception. DESIGN--Randomised group comparison of ethinyloestradiol 100 micrograms plus levonorgestrel 500 micrograms repeated after 12 hours (Yuzpe method); danazol 600 mg repeated after 12 hours; and mifepristone 600 mg single dose. SETTING--Community family planning clinic. SUBJECTS--616 consecutive women with regular cycles aged 16 to 45 years. MAIN OUTCOME MEASURES--Number of pregnancies, incidence of side effects, and timing of next period. RESULTS--The raw pregnancy rates (with 95% confidence intervals) for the Yuzpe, danazol, and mifepristone groups were 2.62% (0.86% to 6.00%), 4.66% (2.15% to 8.67%), and 0% (0% to 1.87%) respectively. Overall, these rates differed significantly (chi 2 = 8.988, df = 2; p = 0.011). The differences between the mifepristone and Yuzpe groups and between the mifepristone and danazol groups were also significant. Side effects were more common and more severe in the Yuzpe group (133 women (70%)) than in either the danazol group (58 (30%)) or the mifepristone group (72 (37%)). The Yuzpe regimen tended to induce bleeding early but mifepristone prolonged the cycle. Three women bled more than seven days late in the Yuzpe group compared with 49 in the mifepristone group. CONCLUSIONS--Mifepristone was effective in reducing expected pregnancy rates and the Yuzpe method also had a clinical effect. Danazol had little or no effect. A further multicentre trial is needed.     

The use of progesterone antagonists and progesterone receptor modulators in contraception

Progesterone antagonists (PAs) and progesterone receptor modulators (PRMs) have contraceptive potential by suppressing follicular development, delaying the surge of luteinizing hormone (LH), retarding endometrial maturation, and promoting endometrial bleeding. Mifepristone, in daily doses of 2-10 mg, blocks the LH surge and ovulation. Many of the studies were conducted in women not at risk of pregnancy, and thus the contraceptive efficacy is not yet known. Nevertheless, there is evidence that daily doses of 2 or 5 mg of mifepristone have contraceptive potential. Because of anovulation, there may be an unopposed estrogen effect on the endometrium, although this risk may be mitigated by the noncompetitive anti-estrogenic activity exhibited by both PAs and PRMs. Low doses of PAs and PRMs, which do not affect ovulation, retard endometrial maturation, indicating that the endometrium is exquisitely sensitive to these compounds. This raises the prospect of endometrial contraception, i.e. prevention of endometrial maturation without disturbing ovulation or producing alterations in bleeding patterns. This approach works well in monkeys but was not found to be very promising when given to women not using contraception. On the other hand, 200 mg mifepristone administered 48 h after the LH surge, which has minimal or no effect on ovulation and bleeding patterns, is an effective contraceptive; yet, it is not a practical approach to contraception. Late luteal phase administration of mifepristone produces menstrual bleeding. However, when mifepristone was administered every month at the end of the cycle either alone or together with prostaglandins, it was not very effective in preventing pregnancy. In contrast, a mifepristone-prostaglandin combination has been shown to be a very effective treatment for occasional menstrual regulation, with vaginal bleeding induced in 98% of pregnant women, with menses delay of 11 days or less. Mifepristone is an excellent agent for emergency contraception when used within 120 h of unprotected intercourse. It is also possible that PAs and PRMs may be used to reduce the occurrence of bleeding irregularities induced by progestin-only contraceptive methods. Both classes of progesterone receptor ligands may also have contraceptive efficacy by having a pharmacological effect on the embryo or altering tubal transport or other aspects of tubal physiology.     

Mifepristone for the prevention of breakthrough bleeding in new starters of depo-medroxyprogesterone acetate

Depo-medroxyprogesterone acetate (DMPA) is an effective injectable contraceptive with worldwide availability. However, it is associated with a high incidence of breakthrough bleeding (BTB) during the first 6 months of use which often leads to discontinuation. Mifepristone is a progesterone receptor antagonist that has been demonstrated to decrease BTB caused by the levonorgestrel subdermal implant (Norplant). The purpose of this study was to determine if mifepristone would decrease BTB in new starters of DMPA. Twenty regularly cycling women who were new starters of DMPA were randomized to receive 50 mg of mifepristone or placebo every 2 weeks for 24 weeks. Percent days of BTB and number of cycles with bleeding intervals > or =8 and > or =14 days were evaluated using daily bleeding diaries. Ovulation was determined by measuring thrice-weekly urinary metabolites of estrogen and progesterone. Endometrial concentrations of ER and PR were determined by immunohistochemistry. Mifepristone significantly decreased the percent days of BTB and the number of cycles with prolonged bleeding intervals when compared to placebo. No subject ovulated in either group. ER immunostaining increased and PR immunostaining decreased after mifepristone treatment. In conclusion, a 50 mg dose of mifepristone taken every 2 weeks decreases the incidence of BTB in new starters of DMPA. This effect may be due to modulation of endometrial estrogen and progesterone receptors.     

Mifepristone: a novel estrogen-free daily contraceptive pill

When the first synthetic progesterone antagonist (mifepristone) was synthesized over 20 years ago, it was clear that it had a potential as an antifertility agent. Research into the use of antiprogestogens for contraception have concentrated on three general approaches: (1) inhibition of ovulation, (2) inhibition of implantation and (3) disruption of implantation or "menstrual induction". The effect of mifepristone on the ovarian and endometrial cycle depends on dose, timing and frequency of administration. Doses of 10 mg per day or more suppress follicular development and estradiol levels. Ovulatory cycles are maintained in the dose of less than 2 mg although there is increased variability in cycle length. The endometrium shows some minor asynchronous changes, although these are not sufficient to prevent pregnancy. We have chosen to investigate daily doses between 2 and 5 mg which inhibit ovulation and menstruation in over 90% of cycles while still maintaining follicular development and levels of estradiol within the range found during the follicular phase. The endometrium shows proliferative or cystic changes lined by a layer of inactive glandular epithelium set in densely packed stroma. There is, however, an absence of proliferative activity as reflected by a reduced mitotic index and Ki67 staining. These unusual histological appearances are associated with downregulation of PR but a massive upregulation of AR in particularly glandular epithelium. The antiproliferative effect of mifepristone is reassuring suggesting that the risk of atypical hyperplasia due to the effect of prolonged exposure to estrogen unopposed by progesterone is low. In a pilot study, there were no pregnancies in 200 months of exposure in 50 women who used this method as their sole method of contraception. Daily mifepristone could provide a novel contraceptive method which should be devoid of the risks associated with estrogen containing combined oral contraceptive (COC), e.g. venous thromboembolism. The health benefits of avoiding the morbidity associated with menstruation are considerable. Recent surveys suggest that amenorrhoea would be popular with many women.     

Mechanisms of action of emergency contraception

The use of levonorgestrel (LNG) alone or combined with ethinylestradiol (Yuzpe regimen), for hormonal emergency contraception (HEC) has been approved in several countries whereas in others it is still under debate or has been rejected under the claim that these formulations abort the developmental potential of the embryo. The issue is whether they act by preventing fertilization or by impeding the successful development of the zygote through and beyond implantation. Until now, published work has left this issue largely unresolved, and this paucity of knowledge sustains heated controversies in many settings. A single study indicates that LNG impairs sperm migration in the genital tract of women in ways that could interfere with fertilization. Several studies in women examined the effects of HEC on the outcome of the leading follicle, but lack of precision in the timing of treatment relative to follicular growth, maturation, or rupture confers great variability and inconsistency of results within and between studies. Nonetheless, results indicate that ovulatory dysfunction may account for the prevention of pregnancy in a large proportion of cases. Studies searching for possible alterations of the endometrium at the time implantation would normally take place, found minimal changes of doubtful significance. Recent studies in animals cast serious doubts that LNG prevents pregnancy by interfering with post-fertilization events. Failure to prevent expected pregnancies is close to 25% in women, and this is likely to be accounted for entirely by treatment given too late to prevent fertilization. The exact mode of action of HEC remains undetermined.     

The return of the pharmaceutical industry to the market of contraception

In the 1980s and 1990s, the litigious climate in the US had a catastrophic effect on sales of many major contraceptives. Although oral contraceptives escaped controversy, the intrauterine device (IUD) and Norplant(R) were two targets of damaging litigation. The IUD was withdrawn from the market in 1985. Since 1994 when the attacks began against Norplant, its US sales have dramatically declined, even though no fault has been found in the method or its development. In general, pharmaceutical companies were extremely hesitant to develop new contraceptives during this period. The bleak outlook, however, began to shift in the late 1990s, as fertility rates began to decrease worldwide and contraceptive users increased. By 2025, 2500 million women will comprise the customer base for contraception. Global pharmaceutical companies are now participating in expanding markets overseas and have launched and continue to develop a range of new long-term reversible, and highly effective, contraceptive products outside the traditional oral contraceptive field. Two new contraceptives on the way to the US market are: Mirena, a levonorgestrel-releasing intrauterine system manufactured by Schering-Leiras; and Implanon, a single implant system manufactured by Organon of the Netherlands. Other birth control methods soon to be launched include: emergency contraceptives, the contraceptive patch, monthly contraceptive injections, mifepristone for medical abortion, and modified oral contraceptives.     

Lessons from an audit of unplanned pregnancies.

To determine the effectiveness of contraceptive use a two year audit of pregnant women registered in one group practice was carried out. The methods of contraception used by women with unplanned pregnancies were studied and the rates of failure assessed. Of the 518 pregnancies during the study, 187 (36%) were unplanned. Unplanned pregnancies were most common in the 15-19 age group (54 out of 187), and women aged under 25 used contraceptives less reliably than women aged 25 and over. The combined pill was the most effective method of contraception in all age groups. The methods that resulted in most unplanned pregnancies were the sheath in women aged 25 and over and incorrect use of oral contraceptive or no contraception in those aged under 25. The fear of side effects was an important reason why women did not use the combined pill, being cited by 22 out of 134 women, and inappropriate medical advice was cited by a further 20 women. More discussion between doctors and patients and readily available information on the use of oral contraceptives might help to reduce the number of unplanned pregnancies.     

Endothelial function across an oral contraceptive cycle in women using levonorgestrel and ethinyl estradiol

Oral contraceptive pills (OCPs) are a popular contraception method. Currently, lower-dose ethinyl estradiol formulations are most commonly prescribed, although they have been linked to increased arterial vascular risk. The aim of this study was to investigate endothelial function in healthy young women using lower-dose ethinyl estradiol OCPs. We examined flow-mediated, endothelium-dependent and nitroglycerin-mediated, endothelium-independent vasodilation of the brachial artery, comparing two doses of ethinyl estradiol/levonorgestrel OCPs in 15 healthy young women on two study days: once during the active phase and once during the placebo phase of an OCP cycle. Group low dose (LD) (n=7) active pills contained 150 microg levonorgestrel/30 microg ethinyl estradiol versus Group very low dose (VLD) (n=8) with 100 microg levonorgestrel/20 microg ethinyl estradiol. Endothelium-dependent vasodilation was lower during the active phase in Group VLD (5.33 +/- 1.77% vs. 7.23 +/- 2.60%; P=0.024). This phase difference was not observed in Group LD (8.00 +/- 0.970% vs. 7.61 +/- 1.07%; P=0.647). Endothelium-independent vasodilation did not differ between phases in either group. Finally, we measured endothelium-dependent vasodilation in two additional women who received 10 microg of unopposed ethinyl estradiol. Endothelium-dependent vasodilation was increased by unopposed ethinyl estradiol compared with the placebo phase (10.88 +/- 2.34% vs. 6.97 +/- 1.83%). These results suggest that levonorgestrel may antagonize the activity of ethinyl estradiol. Thus both the progestin type and estradiol dose need to be considered when assessing arterial vascular risk of OCP use in women.     

Plasma lipids and high density lipoproteins during oral contraception with different combinations of ethinyl estradiol and levonorgestrel.

Seventy-five menstruating women seeking contraceptive advice were randomly allocated to treatment with combined oral contraceptives containing either ethinyl estradiol 50 micrograms + levonorgestrel 250 micrograms (50/250), ethinyl estradiol 30 micrograms + levonorgestrel 150 micrograms (30/150) or ethinyl estradiol 50 micrograms + levonorgestrel 125 micrograms (50/125). The concentrations of cholesterol, triglycerides, phospholipids, high density lipoprotein (HDL)-cholesterol and HDL-phospholipids were determined after one, three and six months and compared to the mean of two determinations of the same parameters before medication. Triglycerides increased by 18--42 per cent after 1--6 months of treatment with 50/125. The HDL-cholesterol and HDL-phospholipids were reduced by 10 per cent during 50/250 treatment. No other parameters showed any consistent alteration in any of the treatment groups. Raised triglyceride concentration and/or decreased HDL concentration increases the risk for cardiovascular disease. It is therefore suggested that in order not to alter the HDL concentration a combined oral contraceptive agent should not contain more gestagen-androgen than corresponding to 125--150 micrograms of levonorgestrel. To avoid a rise of the triglyceride level the weight relation between levonorgestrel and ethinyl estradiol should be about 5:1.     

Termination of pregnancy with reduced doses of mifepristone. World Health Organisation Task Force on Post-ovulatory Methods of Fertility Regulation.

OBJECTIVES--To compare the abortifacient efficacy and side effects of three doses of the antiprogestin mifepristone plus prostaglandin for termination of early pregnancy. DESIGN--Randomised, double blind multicentre trial. SETTING--11 departments of obstetrics and gynaecology and of family planning, mostly in university hospitals, in seven countries. SUBJECTS--1182 women with an early pregnancy (menstrual delay of 7-28 days) requesting abortion. INTERVENTIONS--Single doses of 200 mg, 400 mg, or 600 mg mifepristone followed, 48 hours later, by vaginal pessary of 1 mg of the prostaglandin E1 analogue gemeprost. MAIN OUTCOME MEASURES--Outcome of treatment; duration and subjective amount of menstrual bleeding; side effects and complications; and concentrations of haemoglobin. RESULTS--Outcome was similar with the three doses of mifepristone. Of the 1151 women with known outcome, 95.5% had a complete abortion (364 (93.8%) of those given 200 mg mifepristone, 368 (94.1%) of those given 400 mg, and 367 (94.3%) of those given 600 mg), 3.7% had an incomplete abortion (14 (3.6%), 15 (3.8%), and 14 (3.6%)), 0.3% had a missed abortion (three (0.8%), one (0.3%), and none), and 0.4% had a continuing live pregnancy (two (0.5%), two (0.5%), and one (0.3%)). Of the 43 women who had incomplete abortion, 23 underwent emergency uterine curettage (usually for haemostatic purposes) and three of these women were given a blood transfusion. The numbers of reported complaints, bleeding patterns, and changes in blood pressure and haemoglobin concentrations were similar with the three treatments. CONCLUSIONS--For termination of early pregnancy a single dose of 200 mg mifepristone is as effective as the currently recommended dose of 600 mg when used in combination with a vaginal pessary of 1 mg gemeprost.     

Levonorgestrel antagonism on estrogen-induced pituitary tumors is mediated by progesterone receptors

Using both IN VITRO and IN VIVO approaches, we studied the antagonism exerted by the synthetic progestin levonorgestrel on estrogen-induced prolactinomas, considering that levonorgestrel shows partial androgenic properties and that androgens inhibit estrogen-induced prolactin synthesis and secretion. In the tumors, binding of estrogens to their receptors was competed neither by progesterone receptor ligands nor by androgen receptor ligands, ruling out direct inhibitory effects of these drugs on tumor development. Progestin binding was competed by the progesterone receptor agonists progesterone and levonorgestrel, by the antagonist mifepristone, and also by the androgen dihydrotestosterone, whereas the androgen receptor antagonist hydroxyflutamide was a weak competitor. In addition, both progesterone receptor and androgen receptor ligands competed for binding to androgen receptors. In primary cultures of pituitary tumors, levonorgestrel decreased prolactin secretion, an effect that was blocked by mifepristone but not by hydroxyflutamide. IN VIVO results indicated that levonorgestrel inhibition of both estrogen-induced pituitary weight increment and hyperprolactinemia was reduced by mifepristone, whereas flutamide was unable to block levonorgestrel effects. Our results suggest that even when an interaction of levonorgestrel with androgen receptors in the tumors is possible, the antagonistic effects of levonorgestrel on tumor development and functionality are mediated by progesterone receptors.     

In vitro assessment of some sperm function following exposure to levonorgestrel in human fallopian tubes

Background  

The mechanism of action of levonorgestrel (LNG) as emergency contraception (EC) remains a subject of debate and its effect on sperm function has been only partially explained. The aim of this study was to assess whether LNG at a similar dose to those found in serum following oral intake for EC could affect spermatozoa when exposed to human fallopian tubes in vitro.     

Nomegestrol acetate, a novel progestogen for oral contraception

Nomegestrol acetate (NOMAC) is a potent, highly selective progestogen, which is structurally similar to 19-norprogesterone and characterized as a full agonist at the progesterone receptor, with no or minimal binding to other steroid receptors, including the androgen and glucocorticoid receptors. In animal models, NOMAC demonstrated moderate antiandrogenic activity and strong antiestrogenic activity. In clinical studies, the progestogen was associated with effective suppression of gonadotropic activity and ovulation in premenopausal women, and a neutral impact on hemostasis, lipids, and carbohydrate metabolism. In normal and cancerous human breast tissue, NOMAC has shown favorable effects on estrogen metabolism, and in human breast cancer cell lines in vitro, it does not stimulate cell proliferation. The pharmacologic profile of NOMAC suggested that it would be well suited for combination with a physiologic estrogen in a combined oral contraceptive (COC), with the aim of achieving effective contraception with good cycle control and a favorable safety profile. A monophasic COC containing NOMAC 2.5 mg and 17β-estradiol (E2) 1.5 mg, administered in a 24/4-day regimen, is currently under clinical investigation. In a phase III study, NOMAC/E2 provided consistent and robust ovulation inhibition, with contraceptive effects that compared favorably with those of drospirenone 3 mg/ethinyl estradiol (EE) 30 μg. Investigators for a second phase III study reported less overall impact with NOMAC/E2 on hemostatic, lipid, inflammatory, and carbohydrate metabolism parameters than with levonorgestrel 150 μg/EE 30 μg. These clinical findings are promising; however, full publication of results from the pivotal phase III trials of NOMAC/E2 is pending.     

米菲司酮不同剂量治疗子宫肌瘤的临床疗效观察

目的观察米菲司酮不同给药剂量治疗子宫肌瘤的临床疗效。方法将子宫肌瘤患者分成两组,A组25例,每天服用米菲司酮25mg,B组21例,每天服用米菲司酮10mg,均从月经第一天开始服用,连续三个月。治疗期间每月复查肝、肾功能,治疗开始和结束分别测量子宫和子宫肌瘤的体积和内膜厚度。结果A组肌瘤体积缩小了42.58%(P<0.01),B组肌瘤缩小了41.55%(P<0.01),两者之间无显著性差异(P>0.05)。而两组的药物副作用也无显著差别。结论每日口服米菲司酮10mg可以有效的缩小子宫肌瘤,副作用小。     

Nowadays which emergency contraception? Comparison between past and present: latest news in terms of clinical efficacy, side effects and contraindications

Despite many highly effective methods of contraception are available nowadays, many pregnancies are unintended. Emergency contraception (EC) is the use of drug or device after unprotected intercourse to prevent an unwanted pregnancy. It is a woman's last chance to prevent unintended pregnancy. Nevertheless the confusion about mechanisms of action, side effects, clinical efficacy and controindications makes the intervention underused in every setting investigated. So far levonorgestrel (LNG) has been considered the gold standard for oral EC. Today, a new type of second generation progesterone receptor modulator, ulipristal acetate (UPA) has been proposed as a more effective drug than LNG in prevention of unwanted pregnancies by delaying or inhibiting ovulation; even if many other devices are disposable in commerce. We revised the literature to concern most of the data available on the role of EC and moreover clarifying the available methods, the action windows of the accessible devices, the adverse events and the controindications.