A single dose of mifepristone (200 mg) in the immediate preovulatory phase offers contraceptive potential without cycle disruption

A single dose of mifepristone is an effective emergency contraceptive and has potential as a regular "once-a-month" pill. If given in the early luteal phase, the formation of a secretory endometrium is inhibited or delayed and implantation of the embryo prevented. We have explored the effect of giving the mifepristone just prior to ovulation on the ovarian and endometrial cycle. Seven women with regular menstrual cycles were studied during a control cycle and then in a second cycle when 200 mg mifepristone was given within 24 h of ovulation, i.e., when luteinizing hormone (LH) in serum was >15 IU/L and the dominant follicle was >18 mm. Ovulation was confirmed within 48 h by ultrasound in five of the seven women. The remaining two women had luteinized unruptured follicle. Following mifepristone, menses occurred after a normal luteal phase compared to control cycle (13.7 +/- 0.7 vs. 13.7 +/- 0.9 days). In all subjects the endometrium on LH + 6 in the treatment cycle showed no, or very little, secretory changes, suggesting it was unlikely that pregnancy would have occurred. We conclude that mifepristone could be given as a "once-a-month" contraceptive pill without causing significant disruption in the menstrual cycle in the majority of women for a 4-day period from just prior to ovulation until LH + 3.     

Effect of oral administration of a continuous 18 day regimen of meloxicam on ovulation: experience of a randomized controlled trial

Background

Cyclooxygenase-2 (COX-2) is expressed in all female reproductive organs. Therefore, inhibitors of COX-2 may affect reproductive function. We evaluated the effect of extended administration of meloxicam on ovulation and the menstrual cycle. Our hypothesis was that meloxicam administered from menstrual cycle day 5- 22 could interfere with follicular rupture, without disrupting the menstrual cycle, and could be a potential non-hormonal contraceptive method.

Methods

The study was conducted in 56 healthy sterilized women. Before the onset of treatment and after the end of treatment, participants were observed during a control cycle to ensure that they had progesterone (P₄) serum levels (> 12 nmol/l) consistent with ovulation. Participants were treated for 18 days, during three consecutive cycles. They were randomized to 15 or 30 mg/day. The menstrual cycle was monitored with serial ultrasound and hormone assays in blood.

Results

Fifty-six volunteers completed the study. In 55% of cycles treated with 15 mg/day and in 78% of cycles treated with 30mg/day (p<0.001) we observed dysfunctional ovulation defined as follicular rupture not preceded 24–48 h earlier by an LH peak or preceded by a blunted LH peak (< 21 IU/l) or not followed by an elevated serum P₄ level > 12 nmol/l. Ovulation was observed in 44.6% and in 21.7% of women in the lower dose group and the higher dose group, respectively. There were no differences between the two doses in other parameters measured. There were no serious adverse events and adverse events were not different between doses or between control and treated cycles.

Conclusions

Although administration of meloxicam on menstrual cycle days 5- 22 resulted in a dose-dependent inhibition of ovulation, more than 20% of subjects had normal ovulation with the highest dose.

Implications

Previous studies have shown that oral meloxicam can delay follicle rupture. This study investigated daily oral meloxicam as a non-hormonal contraceptive. Since ovulation occurs in over 20% of cycles even with a high dose of 30 mg daily, it is not likely that the approach would be a highly effective contraceptive strategy.     

Ovulation resumption after medical abortion with mifepristone and misoprostol

Background

As an antiprogestin, mifepristone may have an impact on the return to ovulation in a manner that is not only attributable to its abortifacient activity. Our aim was to measure the time-to-ovulation in women who received mifepristone 200 mg orally and misoprostol 800 mcg vaginally for abortion up to 63 days of gestation.

Study Design

This planned substudy was part of a multicenter randomized trial of mifepristone 200 mg followed immediately or 24 h later by misoprostol 800 mcg vaginally. Women who had successful expulsion of the gestational sac based on ultrasound examination 1 week after mifepristone treatment were enrolled. All subjects used nonhormonal contraception until study completion. Baseline serum progesterone (P) levels were drawn on day 8±1 after mifepristone administration and then twice weekly until the P level was >3 ng/mL, consistent with ovulation. The mean time-to-ovulation was calculated using interval censored regression to address the censoring due to participant discontinuation.

Results

Fourteen (52%) of 27 enrolled women completed the substudy. The longest period of time that a subject who did not complete the study was followed was 29 days. Ovulation occurred 20.6±5.1 (range 8–36) days after mifepristone administration. Time-to-ovulation was not affected by participant age, gestational age, study arm, body mass index or presence or absence of human chorionic gonadotropin.

Conclusions

Return to ovulation following medical abortion with mifepristone and misoprostol occurs on average 3 weeks postabortion. Mifepristone 200 mg does not appear to have a lasting effect on ovarian function. Our results should be contextualized by the small sample size, although this is one of the larger studies on return to ovulation after abortion.     

TwoDay Method: a quick-start approach

Background

Requiring that women wait until the onset of menses to initiate a family planning method is a medical barrier that can result in unintended pregnancies. In the efficacy study of the TwoDay Method, a new fertility awareness-based method of family planning, women were taught the method in the first seven days of their cycles. This study tested a quick-start approach (providing the method at any time in the cycle) to TwoDay Method delivery.

Study Design

In Peru, 167 women were counseled in TwoDay Method use (regardless of cycle day) and followed for up to 7 months. They were interviewed periodically to assess their use of and satisfaction with the method. Simulated clients gauged providers' ability to correctly counsel in method use at different times of the cycle.

Results

No significant differences were observed in correct use, continuation rates, and acceptability of the method among women who were counseled at different points in the cycle; quality of counseling was not undermined by the quick-start approach.

Conclusions

There is no need to limit delivery of the TwoDay Method to the first seven days of the menstrual cycle.     

Timing and indication for curettage after medical abortion in early pregnant women with prior uterine incision

Background

Termination of pregnancy is an important and necessary back-up method for family planning services in many countries. The combination of mifepristone and misoprostol is a widely used alternative to surgical evacuation of the uterus in early pregnancy; however, there are few reports about medical abortion in women with a prior uterine incision and few studies have described curettage occurring as part of the procedure and an indication for the intervention. Curettage in a prior uterine incision can increase operative complications. The purpose of this study was to investigate whether vaginal bleeding intervals, routine ultrasound scan and serum β-hCG test after medical abortion could accurately identify women with uterine scars who would require curettage.

Methods

Six hundred sixty-eight women with a uterine scar and at up to 49 days of gestation underwent a medical abortion with mifepristone and misoprostol. Each woman took 50 mg and 25 mg of mifepristone orally in the morning and in the evening, respectively, for 2 days and 600 mcg of misoprostol orally on the third day.

Results

Of the 668 women, 6 (0.9%) were lost to follow-up. The overall complete abortion rate was 91.7%; 55 women underwent curettage, including 2 women with heavy bleeding, 3 women with ongoing pregnancy and 34 women with incomplete abortion. The incomplete abortion rate was significantly greater in women with persistent bleeding lasting 21 days than in women with persistent bleeding lasting 14 days (p<.001), and the overall sensitivity and specificity of vaginal bleeding interval (21 days) were 97.1% and 75%, respectively. The incomplete abortion rate was also greater in women whose serum β-hCG was ≥500 IU/L than in women whose serum β-hCG was <500 IU/L (p<.001), and the overall sensitivity and specificity of serum β-hCG (≥500 IU/L) were 97.1% and 62.5%, respectively. Moreover, the incomplete abortion rate was greater in women with an endometrial thickness ≥15 mm than in women with an endometrial thickness <15 mm (p<.001), and the overall sensitivity and specificity of endometrial thickness (≥15 mm) were 94.1% and 75%, respectively. No complication occurred.

Conclusions

The combination of mifepristone and misoprostol was found to be a safe and effective method to terminate early pregnancy in women with a previous cesarean delivery. If a woman with a prior uterine incision experienced vaginal bleeding intervals ≥21 days and/or had a bilayer endometrial thickness ≥15 mm and/or serum β-hCG ≥500 IU/L after a medical abortion, then she should undergo curettage.     

Contraceptive efficacy of emergency contraception with levonorgestrel given before or after ovulation

Background

The contraceptive efficacy of emergency contraceptive pills containing levonorgestrel (LNG-EC) has been estimated in most previous studies by judging the day of ovulation from presumptive menstrual cycle data, thus providing poorly reliable estimates.

Methods

In the present study, the efficacy of LNG-EC was determined in 393 cycles by dating ovulation on the basis of reliable hormonal and ovarian parameters validated by a database constructed in a separate study. In addition, the efficacy was determined separately for cycles in which LNG-EC was given before or after ovulation.

Results

For the 148 women who had sexual intercourse during the fertile days, the overall accumulated probability of pregnancy was 24.7, while altogether 8 pregnancies were observed. Thus, the overall contraceptive efficacy of LNG-EC was 68%. Among the 103 women who took LNG-EC before ovulation (days −5 to −1), 16 pregnancies were expected and no pregnancy occurred (p<.0001). Among the 45 women who took LNG-EC on the day of ovulation (day 0) or thereafter, 8 pregnancies occurred and 8.7 were expected (p=1.00). These findings are incompatible with the inhibition of implantation by LNG-EC in women. The same cases were also analyzed using the presumptive menstrual cycle data, and important discrepancies were detected between the two methods.

Conclusion

The efficacy of LNG-EC has been overestimated in studies using presumptive menstrual cycle data. Our results confirm previous similar studies and demonstrate that LNG-EC does not prevent embryo implantation and therefore cannot be labeled as abortifacient.     

Menstrual effects among women exposed to polychlorinated biphenyls and dibenzofurans

Background

Polychlorinated biphenyls (PCBs), dibenzofurans (PCDFs), and dibenzo-dioxins (PCDDs) may affect the female reproductive system in humans. A mass poisoning occurred in Taiwan due to PCBs/PCDFs-contaminated cooking oil, and was called the Yucheng (oil-disease in Chinese). We aimed to determine whether Yucheng women were affected in their menstruation.

Methods

After the event, we followed the exposed individuals and an age-matched neighborhood reference group. Menstrual cycle characteristics and age at menarche were obtained by a telephone interview. We used multiple linear and logistic regression to examine the association between PCBs/PCDFs and menstrual cycle characteristics, after adjusting for confounding factors.

Results

Totally 445 women responded satisfactorily and were included in the analyses of menstrual characteristics. Menstrual cycle irregularity and dysmenorrheal did not differ between Yucheng and referents. Yucheng women's menstrual cycles were 0.5 (95% CI: 0.0–0.5; p=0.03) days shorter than those of the referents. The Yucheng women with skin lesions caused by PCBs/PCDFs were more prominently affected, with the cycles 1.2 days shorter than the referents. Yucheng women exposed to PCBs/PCDFs at the premenacheal period had reduced cycle length (−0.7 day, 95% CI: −1.4 to 0.0; p=0.04) and longer days of menstrual flow (0.5 day, 95% CI: 0.0–1.0; p=0.04). Among those women who were exposed at an age of 5–9 years, menarche started slightly earlier with borderline significance.

Conclusions

Shorter menstrual cycle length and a longer duration of bleeding in each cycle were found among women previously exposed to PCBs/PCDFs. These effects were more obviously observed among those exposed at premenarcheal ages.     

Contraceptive failure related to estimated cycle day of conception relative to the start of the last bleeding episode

Background

The objective of this study was to estimate the menstrual cycle day of conception in women presenting for abortion.

Study Design

This was a retrospective chart survey in two urban free-standing abortion clinics.

Results

There were 913 charts reviewed of women presenting for an abortion at less than 63 days' gestation as determined by endovaginal ultrasound who were “sure” of the date of their last normal menstrual period. The estimated mean cycle day of conception determined by sonographically estimating length of gestation was 14.6. There were 26 (26.3%) of 99 women using cyclic hormonal contraception who conceived before 10 days after the onset of withdrawal bleeding compared to 100 (14.7%) of 679 who conceived before 10 days after the onset of their last menstrual period who were using all other forms of contraception, including “none” (p=.005). No other differences in the proportions conceiving early in the cycle were observed with respect to age, ethnicity or obesity.

Conclusion

These data suggest that there is a sizeable subset of women who ovulate earlier after onset of withdrawal bleeding when using 21/7 hormonal contraceptives than after onset of menses when not using hormonal contraception. It is possible that women using hormonal contraceptives may have a higher risk of pregnancy if they ovulate sooner after the onset of bleeding.     

Association between characteristics of current menses and preference for induced amenorrhea

Background

Several studies suggest that many women would prefer to avoid menses altogether, but few studies have examined the social or clinical predictors of such preference.

Study Design

In total, 1224 healthy women of reproductive age were surveyed in Brazil, Germany and the United States regarding social, menstrual and reproductive characteristics and preferences for various dimensions of menstruation, including the ideal interval between menses. The extent to which a preference to never bleed was predicted by current experiences with menses was evaluated.

Results

Long menses, menstrual pain and a perceived high cost of pads and tampons were predictive of preferring amenorrhea over all other menstrual patterns after controlling for age, parity and education. Independent significant associations were also found with increasing degrees of life stress and ever use of injectable contraceptives.

Conclusion

A negative experience with menstruation, a high ranking of life stress and ever use of injectable contraception were independently associated with a preference to avoid menses altogether.     

A randomized study on pharmacodynamic effects of vaginal rings delivering the progesterone receptor modulator ulipristal acetate: research for a novel estrogen-free,method of contraception

Objective

To determine whether a 3-month contraceptive vaginal ring (CVR) delivering ulipristal acetate (UPA) can inhibit ovulation in 90% of cycles.

Study Design

This was a randomized dose-finding parallel group clinical trial. Fifty-five healthy women with normal ovulation at baseline were randomized to receive a low-dose (1500 μg/day) or a high-dose (2500 μg/day) UPA-CVR for two consecutive 12-week treatment periods, followed by a recovery cycle. A subgroup of women received levonorgestrel (LNG) 1.5 mg orally twice (at the end of both 12-week ring periods) or once (at the end of the 24-week treatment). The primary outcome was ovulation suppression assessed by transvaginal ultrasound and hormone levels. Secondary outcomes included endometrial safety and bleeding patterns.

Results

All subjects showed normal ovulation at baseline and recovery. Ovulation suppression was seen in 81.8% (95% CI: 73.3%, 88.5%) and 86.1% (95% CI: 78.1%, 92%) of treatment cycles with low and high-dose, respectively. Benign progesterone receptor modulator associated endometrial changes (PAEC) were seen during treatment; 78.8% at week 24, but resolved at recovery cycle. A few cases of heavy bleeding occurred near the end of the 24-week treatment, but a single dose of LNG every 12 weeks reduced the increase in endometrial thickness during the second treatment period and prevented excessive bleeding.

Conclusion

The 3-month UPA-CVR may become an effective long-acting, user-controlled estrogen-free contraceptive. The greatest suppression of ovulation was seen with the 2500-μg/day ring.

Implications

The 3-month CVR delivering UPA 2500 μg/day can become an effective user-controlled estrogen-free contraceptive method. Benign PAEC during treatment returns to normal after discontinuation. The prevention of occasional excessive withdrawal bleeding, either by a progestin or by using higher UPA levels to increase follicle suppression may permit prolonged treatment.     

Feasibility of assessing the safety and effectiveness of menstrual regulation medications purchased from pharmacies in Bangladesh: a prospective cohort study

Objective

To assess the feasibility of following up women who purchase mifepristone+misoprostol or misoprostol-only from pharmacies in order to measure the safety and effectiveness of self-administration of menstrual regulation.

Menstrual problems and contraception in women of reproductive age receiving oral anticoagulation

Background

Oral anticoagulation is associated with increased bleeding complications. The aim of this study was to assess the changes in menstrual loss and pattern in women taking anticoagulant treatment.

Study Design

Women on oral anticoagulant (OA) treatment at the Royal Free Hospital were interviewed and completed a questionnaire about their menstrual cycle before and after commencing oral anticoagulation treatment. They were then asked to complete a pictorial bleeding assessment chart (PBAC) during their next menstrual bleeding episode.

Results

Fifty-three women between the ages of 20 and 50 years participated in the study. Of these, 47 women completed a PBAC. The mean duration of menstruation increased from 5 days before starting OA therapy to 7 days after the commencement of treatment. Thirty-one (66%) of the 47 women who completed the PBAC had a score that was greater than 100. The number of women who experienced flooding or clots during menstruation and intermenstrual or postcoital bleeding also increased. In total, 29 (54.7%) women changed their method of contraception during OA treatment. Seventeen women who did not want to become pregnant were not using contraception, including 10 women who were on hormonal contraception prior to starting anticoagulant therapy.

Conclusion

Women of reproductive age experience heavy and prolonged menstrual bleeding whilst on OA therapy. Women of reproductive age on OA therapy should be monitored for menstrual disorders to ensure that prompt and appropriate treatment is instituted. Advice about appropriate contraception should also be part of the medical care provided for these women. Barrier contraception, sterilization and progestin-only contraception are all suitable methods of contraception in this patient group.     

Outcomes of medical abortion through 63 days in women with twin gestations

Background

Twin gestation is not considered a contraindication to medical abortion with mifepristone and misoprostol. However, data comparing the efficacy of medical abortion for singleton gestations as compared with multiple gestations are limited. We examined medical abortion outcomes for twin gestations through 63 days.

Study Design

We performed a secondary analysis of treatment efficacy and side effects using pooled data from two randomized medical abortion trials. All subjects received mifepristone 200 mg orally and misoprostol 800 mcg vaginally. Outcomes in women with singleton and twin gestations were compared.

Results

Of 2208 subjects, 24 (1.1%) women had twins. Treatment success was not statistically different for twin and singleton gestations (91% vs. 97%, p=.19). Perceived bleeding and pain were not significantly different between groups.

Conclusions

Treatment success of medical abortion for twins is not significantly different than for singletons, although small differences cannot be excluded due to the limited number of twins.     

A prospective randomized trial comparing low-dose ethinyl estradiol and drospirenone 24/4 combined oral contraceptive vs. ethinyl estradiol and drospirenone 21/7 combined oral contraceptive in the treatment of hirsutism

Background

A prospective randomized trial was conducted to compare the clinical efficacy of two oral contraceptives containing drospirenone in the treatment of hirsutism in women.

Study Design

Fifty women with moderate to severe hirsutism were recruited. Three women were lost to follow-up. Twenty-four patients received oral 0.03 mg ethinyl estradiol and 3 mg drospirenone 21/7 regimen (Group 1) for 6 months. Another group of 23 patients received oral 0.02 mg ethinyl estradiol and 3 mg drospirenone 24/4 regimen (Group 2) for 6 months. Hirsutism was assessed after 6 months using the Ferriman–Gallwey (F-G) scoring system. Hormonal levels after 6 months of both therapies were compared with baseline values and each other.

Results

An improvement in the F-G scores for hirsutism (mean±SD) was observed in Group 1 (17.3±5.2 to 8.7±2.5, p<.001) and in Group 2 (17.5±4.8 to 7.9±2.8, p<.001). Pre- and post-treatment hirsutism scores were comparable between the groups (p>.05). Total and free testosterone levels decreased significantly after the therapy in both groups. The sex hormone-binding globulin levels increased significantly in both groups during the 6-month period.

Conclusion

The treatment of hirsutism with both combined oral contraceptives (COCs) containing drospirenone offered comparable effects and was well tolerated.     

The M-OVIN study: does switching treatment to FSH and / or IUI lead to higher pregnancy rates in a subset of women with world health organization type II anovulation not conceiving after six ovulatory cycles with clomiphene citrate – a randomised controlled trial

Background

Clomiphene citrate (CC) is first line treatment in women with World Health Organization (WHO) type II anovulation and polycystic ovary syndrome (PCOS). Whereas 60% to 85% of these women will ovulate on CC, only about one half will have conceived after six cycles. If women do not conceive, treatment can be continued with gonadotropins or intra-uterine insemination (IUI). At present, it is unclear for how many cycles ovulation induction with CC should be repeated, and when to switch to ovulation induction with gonadotropins and/or IUI.

Methods/Design

We started a multicenter randomised controlled trial in the Netherlands comparing six cycles of CC plus intercourse or six cycles of gonadotrophins plus intercourse or six cycles of CC plus IUI or six cycles of gonadotrophins plus IUI.Women with WHO type II anovulation who ovulate but did not conceive after six ovulatory cycles of CC with a maximum of 150 mg daily for five days will be included.Our primary outcome is birth of a healthy child resulting from a pregnancy that was established in the first eight months after randomisation. Secondary outcomes are clinical pregnancy, miscarriage, multiple pregnancy and treatment costs. The analysis will be performed according to the intention to treat principle. Two comparisons will be made, one in which CC is compared to gonadotrophins and one in which the addition of IUI is compared to ovulation induction only. Assuming a live birth rate of 40% after CC, 55% after addition of IUI and 55% after ovulation induction with gonadotrophins, with an alpha of 5% and a power of 80%, we need to recruit 200 women per arm (800 women in total).An independent Data and Safety Monitoring Committee has criticized the data of the first 150 women and concluded that a sample size re-estimation should be performed after including 320 patients (i.e. 80 per arm).

Discussion

The trial will provide evidence on the most effective, safest and most cost effective treatment in women with WHO type II anovulation who do not conceive after six ovulatory cycles with CC with a maximum of 150 mg daily for five days. This evidence could imply the need for changing our guidelines, which may cause a shift in large practice variation to evidence based primary treatment for these women.

Trial registration number

Netherlands Trial register NTR1449

     

The effect of levonorgestrel-releasing intrauterine device on menorrhagia in women taking anticoagulant medication after cardiac valve replacement

Background

This study was conducted to evaluate the effect of levonorgestrel-releasing intrauterine devices (LNG-IUDs) on menorrhagia in patients receiving anticoagulant therapy after cardiac valve replacement.

Study Design

Forty women with menorrhagia who underwent cardiac valve replacement and were taking anticoagulant medication were enrolled in the study. The women were randomly divided into two groups: LNG-IUDs were inserted into 20 women in Group 1 over the first 3 days of menstrual bleeding, while the women in Group 2 were followed without any intervention. The activated partial thromboplastin time, prothrombin time, international normalized ratio, hematocrit level, hemoglobin level, ferritin level and pictorial bleeding assessments for the quantity of menstrual bleeding were recorded.

Results

Three months after insertion of LNG-IUDs, the women in Group 1 had a significant decrease in blood loss and higher hemoglobin, hematocrit and ferritin values. No difference was detected for these parameters in the control group at the third and sixth months of the study. Coagulation parameters did not differ between the two groups.

Conclusion

LNG-IUDs can be considered as an effective non-surgical treatment for menorrhagia in women receiving anticoagulant therapy after cardiac valve replacement.     

最小剂量米非司酮配伍米索前列醇抗早孕临床预试验报告

为探索米非司酮抗早孕的最小有效剂量,对100例停经≤56天孕妇服不同剂量米非司酮进行了临床预试验。分为四组停经≤35天受试者分次服米非司酮7mg,配伍米索600μg,完全流产率95.4％;35天<停经≤56天受试者分次服米非司酮100mg,及125mg两组完全流产率均高于93％,而顿服米非司酮100mg完全流产率仅73.3％,与另三组有显著差异。提示:①米非司酮75mg分次服抗早孕具有良好的抗早孕前景,副反应小,可节省服药妇女经费。②顿服米非司酮100mg临床效果不佳。③分次服米非司酮100mg,停经天数可延长到56天,仍有良好流产效果。