A prospective, randomized, pharmacodynamic study of quick-starting a desogestrel progestin-only pill following ulipristal acetate for emergency contraception.

STUDY QUESTION: Is there a pharmacodynamic interaction between ulipristal acetate (UPA) 30 mg for emergency contraception and a daily progestin-only contraceptive pill, desogestrel (DSG) 0.75 mg, when initiated the next day? SUMMARY ANSWER: In this study, DSG impaired the ability of UPA to delay ovulation, but UPA had little impact on the onset of contraceptive effects due to DSG. WHAT IS KNOWN ALREADY: UPA is a progesterone receptor modulator used for emergency contraceptive (EC) at the dose of 30 mg. UPA delays ovulation by at least 5 days when administered in the mid to late follicular phase. In theory, potent progestins could reactivate progesterone signaling that leads to follicle rupture, thereby impacting the effectiveness of UPA as EC. In addition, UPA could alter the onset of the contraceptive effect of progestin-containing contraceptives started immediately after UPA. STUDY DESIGN, SIZE, DURATION: A single-blind (for observer), placebo-controlled, partial crossover study was conducted in two sites [Dominican Republic (DR) and the Netherlands (NDL)] over 11 months from October 2012 to September 2013. Healthy female volunteers participated in two of the three treatment cycles separated by a washout cycle. Treatment combinations studied were as follows: (i) a single 30 mg dose of UPA followed by 75 µg per day DSG for 20 days, (ii) a single 30 mg dose of UPA followed by 20 days of placebo matching that of DSG (PLB2) or (iii) one tablet of placebo-matching UPA (PLB1) followed by 75 µg per day DSG for 20 days. Participants were randomized to one of the three treatment sequences (UPA + DSG/UPA + PLB2, PLB1 + DSG/UPA + DSG and UPA + PLB2/PLB1 + DSG) when a lead follicle was ≥ 14 to <16 mm diameter on transvaginal ultrasound imaging (TVU). PARTICIPANTS/MATERIAL, SETTING, METHODS: A total of 71 women were included, and 49 were randomized to a first treatment combination of the three period sequences (20 in the DR and 29 in the NDL); 41 of the 49 continued and completed two treatment combinations (20 in the DR and 21 in the NDL). MAIN RESULTS AND THE ROLE OF CHANCE: Initiating DSG treatment the day after UPA significantly reduced the ovulation delaying effect of UPA (P = 0.0054). While ovulation occurred in only one of the 29 UPA-only cycles (3%) in the first 5 days, it occurred in 13 of the 29 (45%) UPA + DSG cycles. LIMITATIONS, REASONS FOR CAUTION: This was a small, descriptive, pharmacodynamic study in which some findings differed by study site. Distinguishing between a cystic corpus luteum and a luteinized unruptured follicle (LUF) by TVU was difficult in some cases; however, the investigators reached consensus, when the study was still blinded, regarding ovulation based on hormone levels and careful review of daily TVU images. WIDER IMPLICATIONS OF THE FINDINGS: Initiating the use of a DSG progestin-only pill (POP) immediately after UPA reduces the ability of UPA to delay ovulation and thus may decrease its efficacy as EC. If starting a DSG POP after using UPA for EC, and possibly any progestin-only method, consideration should be given to delaying for at least 5 days after UPA intake in order to preserve the ovulation delaying effects of UPA.

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.

Randomized trial to evaluate contraceptive efficacy, safety and acceptability of a two-rod contraceptive implant over 4 years in the Dominican Republic.

OBJECTIVE: Sino-implant (II) is a contraceptive implant that had a commodity price one-third of the competing products a decade ago. To make Sino-implant (II) more widely available, we conducted a trial to collect safety and efficacy data required for World Health Organization (WHO) prequalification, a quality standard allowing global donors to procure a pharmaceutical product. STUDY DESIGN: This was a randomized controlled trial allocating 650 participants to either Sino-implant (II) or Jadelle®. Participants were seen at 1 and 6 months, and then semiannually. The primary efficacy measure was the pregnancy Pearl Index [number of pregnancies per 100 women-years (WY) of follow-up] in the Sino-implant (II) group during up to 4 years of implant use. RESULTS: For the primary outcome, Sino-implant (II) had a 4-year Pearl Index of 0.74 (95% confidence interval, 0.36-1.37) compared to 0.00 (95% confidence interval, 0.00-1.04) for Jadelle®. The Sino-implant (II) pregnancy rate was significantly higher in the fourth year (3.54 per 100 WY) than in the first 3 years combined (0.18 per 100 WY; p <.001). Total levonorgestrel concentrations were equivalent between groups at month 12, but were 19%, 22% and 32% lower in the Sino-implant (II) group at months 24, 36 and 48, respectively (p <.001 at each time point). Safety and acceptability of the two products were similar, while providers documented significantly higher breakage rates during removal of Sino-implant (II) (16.3% vs. 3.1%; p <.001). CONCLUSION: Based on these results, WHO prequalified Sino-Implant (II) with a 3-year use label in June 2017, 2 years shorter than the 5-year duration of Jadelle®. IMPLICATIONS: WHO prequalification allows global donors to procure Sino-implant (II), which means women in many low resource countries will have greater access to highly effective and acceptable contraceptive implants. Our study noted important clinical differences, including shorter duration of high effectiveness with Sino-implant (II) when compared to the other available two-rod system, Jadelle®. Introduction strategies should include appropriate training on these differences.

A prospective, open-label, multicenter study to assess the pharmacodynamics and safety of repeated use of 30 mg ulipristal acetate.

OBJECTIVE: Ulipristal acetate (UPA) 30 mg is safe and effective for emergency contraception (EC). This prospective open-label exploratory study was conducted to obtain additional data on the pharmacodynamic effects of repeated dose of UPA 30 mg during an 8-week period (effects on ovulation inhibition, hormonal levels, endometrium and cervical mucus). Safety and tolerability data of repeated use of UPA EC were also collected. STUDY DESIGN: A total of 23 healthy female, healthy sterilized women participated in two substudies receiving UPA for 8 consecutive weeks. In substudy 1, UPA 30 mg was administered every 7 days (Q7D n=12); while in substudy 2, every 5 days (Q5D n=11). Subjects were monitored three times a week in a baseline cycle and during treatment with transvaginal ultrasounds, hormonal measurements and cervical mucus evaluation. Laboratory safety measurements and standard surrogate thrombosis risk markers were measured at baseline and within a few days of the last tablet. A luteal phase endometrial biopsy was taken in the baseline cycle and posttreatment. RESULTS: A total of 11/12 (91.7%) and 8/11 (72.7%) of the subjects ovulated at least once in substudy Q7D and Q5D, respectively, with similar, normal hormonal profiles. No effect on cervical mucus was observed. All biopsies were classified as benign in both substudies; 5/11 biopsies on Q5D posttreatment were classified as nonphysiological with some of typical progesterone receptor modulator-associated endometrial changes. UPA was well tolerated in both treatment arms while clinical laboratory results and surrogate thrombosis markers were reassuring. CONCLUSIONS: Repeat use of 30 mg oral UPA every 5 or 7 days for 8 weeks initially delays follicular rupture but ovulation eventually occurs with time in most subjects. Safety data indicate that UPA 30 mg could be safely administered if needed more than once for EC in a given menstrual cycle. IMPLICATIONS: These data demonstrate that repeated use of UPA 30 mg is safe. However, ovulation eventually occurs in a high proportion of women in spite of repeated treatments in both studied regimens. Nevertheless, since the stage of follicular development of women seeking initial or repeat EC use is generally unknown, the repeated use of UPA may still delay follicular rupture and prevent an unintended pregnancy in the event of further unprotected intercourse.

Comparative study on the efficacy and acceptability of two contraceptive pills administered by the vaginal route: an international multicenter clinical trial.

The efficacy and acceptability of two widely used oral contraceptive tablets, one containing 250 mg levonorgestrel and 50 micrograms ethinyl estradiol and the other containing 150 micrograms desogestrel and 30 micrograms ethinyl estradiol, administered by the vaginal route were compared in 1055 women studied over 12,630 woman-months of vaginal contraceptive pill use. This multicenter clinical trial was performed in nine countries of the developing world by the "South to South Cooperation in Reproductive Health," an organization founded by scientists from the Third World working in the area of reproductive health, and the study was developed and coordinated by one of these centers. The findings of this study confirm the efficacy of both these tablets when administered by the vaginal route. Involuntary pregnancy rates at 1 year of 2.78 for subjects in the levonorgestrel group and 4.54 for subjects the desogestrel group showed no statistically significant difference between the two groups. However, total discontinuation rates of 47.01 for subjects in the levonorgestrel group and 56.33 for subjects in the desogestrel group showed a statistically significant difference between the two groups, and discontinuation rates attributable to prolonged bleeding of 0.6 for subjects in the levonorgestrel group and 3.2 for subjects in the desogestrel group were also significantly higher in the group of subjects using the desogestrel vaginal contraceptive pill. Blood pressure remained at admission values throughout treatment. A statistically significant weight increase from admission values occurred in both groups of subjects.

PIP: Efficacy and acceptability of 2 combined oral contraceptive pills administered vaginally are summarized. This is the 1st collaborative trial published by the South to South Cooperation in Reproductive Health. 1055 women participated in 12,630 cycles, in 9 countries, from June 1988 to May 1991. The pills were commercially available tablets containing 50 mcg ethinyl estradiol and 250 mg levonorgestrel (Schering AG, Sao Paulo, Brazil), or 30 mcg ethinyl estradiol and 15 mcg desogestrel (Organon, Sao Paulo, Brazil). Subjects were aged 17-39 younger and of lower parity from Mexico and Dominican Republic and older from Egypt and China. All had at least 1 pregnancy. 675 participated for 6 months, 470 for 1 year, 364 for 18 months, and 210 for 2 years. The 1-year discontinuation rate averaged 47.01% for the levonorgestrel group and 56.33% for the desogestrel group (p = 0.0061); 2-year discontinuation rates were 48.01% and 69.36, respectively, explained in part by higher involuntary pregnancy rates and prolonged bleeding rates in the desogestrel group. The most common medical reasons for stopping contraception were unplanned pregnancy, vaginal or vulval irritation, nausea, vaginal discharge and headache. Vaginal irritation was reported by 1%, 9 in each group. There were 32 pregnancies, 14 in the levonorgestrel and 18 in the desogestrel group. 17 were in missed pill cycles and the rest were method failures, 6 in the levonorgestrel group and 9 in the desogestrel group. The Pearl index varied from 0 in Nigeria to 12.24 in Mexico, and was 2.45 for levonorgestrel vs. 3.74 for desogestrel. There was a wide variation in discontinuation rates by center: Brazil and China had few, while many women from Dominican Republic, Mexico and Zambia left the study. Bleeding problems were common complaints, more so in the desogestrel group. There were 363 women with intermenstrual bleeding (only once in 80%), 148 with spotting (only twice in 65%). Bleeding duration was significantly less in pill cycles than baseline, pressure. Women gained an average of 1 kg over 2 years, more in the desogestrel group. The pregnancy rate of 2.78 is within the range reported for levonorgestrel rings.

A comparison of "U" and standard techniques for Norplant removal.

OBJECTIVE: To evaluate the "U" technique versus the manufacturer-recommended technique for Norplant removal. METHODS: We conducted a randomized comparison of the manufacturer-recommended method of removal and the "U" technique. The latter involves an incision between and parallel to the third and fourth implants and uses a modified vasectomy clamp to remove the implants by pulling perpendicular to the implant's axis. RESULTS: Twenty-one physicians (three experienced, 18 inexperienced) performed 200 Norplant removals. Inexperienced physicians took significantly less time for removal using the "U" technique than the standard technique (7.9 versus 10.5 minutes), even after controlling for other factors. Experienced physicians also required less time for removal using the "U" technique (3.1 versus 3.7 minutes), but the difference was not statistically significant after controlling for other factors. Both experienced and inexperienced physicians broke implants more frequently using the standard technique, although the difference was significant only for experienced physicians (relative risk 3.6, 95% confidence interval 1.2, 10.8). No differences were noted between the techniques with respect to tissue damage or patient reports of pain during or after removal. CONCLUSIONS: These results suggest that the "U" technique is an improvement over the standard technique, particularly for personnel who are not highly experienced in Norplant removal.

Prospective study of the pituitary-ovarian function after tubal sterilization by the Pomeroy or Uchida techniques.

Surgical sterilization has become one of the most widely used methods of fertility regulation in the world. A common concern is the not yet clarified possible disturbance of the ovarian function resulting from the surgical procedure. A prospective study was carried out to contribute toward answering this question. Twenty subjects were enrolled in a longitudinal study of ovarian endocrine function before, and 2 and 6 months after, tubal ligation. The Pomeroy technique, which may compromise ovarian circulation, and the Uchida technique, which is free of this risk, were used randomly. Eight women who underwent to the Pomeroy technique and 9 who underwent the Uchida technique completed the protocol. Luteinizing hormone, follicle-stimulating hormone, estradiol, and progesterone were measured daily from days 10 through 18 of the cycle and every other day until the onset of the next menses. No change in any of the hormones studied was observed, with the exception of a significant increase in progesterone 2 months after tubal ligation by the Uchida technique.

Effect of preovulatory insertion of Norplant implants over luteinizing hormone secretion and follicular development.

OBJECTIVE: To determine whether the process of ovulation could be interrupted by the insertion of Norplant implants (Leiras Pharmaceuticals, Turku, Finland) in the advanced preovulatory phase. DESIGN: Prospective study. SETTING: The Department of Biomedical Research at the Family Planning Clinic of PROFAMILIA, Santo Domingo, Dominican Republic. PATIENTS: Healthy women of reproductive age, requesting Norplant implants contraception. Thirteen of 15 women volunteers who were admitted completed the study. INTERVENTIONS: Norplant implants were inserted when the dominant follicle reached a mean diameter of 16 mm, based on serial vaginal ultrasounds (US) beginning on day 10 of the cycle. Blood samples for determination of E2, P, LH, and levonorgestrel, were taken and vaginal US performed at 0, 4, 24, 48, and 72 hours after insertion. If follicle rupture had not occurred at 72 hours after insertion, blood sampling and US were done three times per week during 2 additional weeks. RESULTS: Follicle rupture occurred in 11 of 13 subjects within 72 hours after insertion, with the exception of 1 subject in whom rupture occurred between 72 and 192 hours. Two women already had an LH peak at the time of insertion. In 9 of the remaining 11 women, a shortlasting, blunted LH surge was observed at 4 hours postinsertion. In the remaining two women, who had the lowest E2 levels, ovulation was inhibited, and a persistent follicle developed without luteinization. CONCLUSIONS: The insertion of Norplant implants in the advanced follicular phase will not inhibit ovulation if sufficient E2 priming has occurred. On the contrary, the exogenous progestin may rapidly foster ovulation shortly after.

PIP: 15 healthy women of reproductive age requesting Norplant were admitted into this prospective study conducted to determine whether the ovulation process can be interrupted by the insertion of Norplant implants during the advanced preovulatory phase. The implants were inserted when the dominant follicle reached a mean diameter of 16 mm, based upon serial vaginal ultrasounds (US) beginning day 10 into the cycle. Blood samples to determine levels of E(2), P, LH, and levonorgestrel were taken and vaginal US performed at 0, 4, 24, 48, and 72 hours after insertion. If follicle rupture had not occurred by 72 hours after insertion, blood sampling and US were done three times per week for two additional weeks. Follicle rupture occurred in 11 of the 13 subjects who completed the study within 72 hours after insertion, except for one subject who experienced rupture at 72-192 hours. Overall, it was determined that the insertion of Norplant implants during the advanced follicular phase will not inhibit ovulation if sufficient E(2) priming has occurred. The exogenous progestin, however, may rapidly foster ovulation shortly thereafter.

Norplant implants: the mechanism of contraceptive action.

OBJECTIVE: To determine if fertilization occurs unnoticed among Norplant users who are ovulatory. DESIGN: Serial blood samples were obtained during 1 month from sexually active Norplant users experiencing regular menstrual bleeding patterns and a control group of noncontracepting women trying to conceive. The sequential blood samples were assayed for the presence of human chorionic gonadotropin (hCG). SETTING: All samples were obtained from women receiving contraceptive service and health care at the Center for Research and Services in Human Reproduction and Contraception, Santo Domingo, The Dominican Republic. Assays for hCG were performed at the Department of Biomedical Sciences, University of Tampere, Finland. PATIENTS, PARTICIPANTS: A total of 32 women using Norplant implants were enrolled in the treatment group, and 20 women of proven fertility who were attempting to conceive served as a control group. INTERVENTIONS: Duration of Norplant use was as follows: 4 in the 2nd year of use, 13 in the 3rd year, 11 in the 4th year, 3 in the 5th year, and 1 in the 7th year. MAIN OUTCOME MEASURE: The determination of pregnancy was based on the presence of hCG in the luteal phase, using a sensitive and specific immunoenzymatic assay that can detect dimeric hCG as early as 7 days after ovulation. RESULTS: Nine pregnancies were detected. All were in the control group trying to conceive. Six of these advanced to clinical pregnancies, and three did not proceed beyond the next expected menses. None of the Norplant users had evidence of hCG production, whether the observed cycles were anovulatory or ovulatory. The probability of finding no pregnancies in the ovulatory months at risk among Norplant users is between 1 in 50 and 1 in 150,000. The null hypothesis that Norplant users conceive at a natural rate can be rejected at the 0.05 level. CONCLUSION: Interruption of early pregnancy (menstrual abortion) does not play a role in the mechanism of action of Norplant contraceptive implants.

PIP: This study sought to determine if fertilization can occur unnoticed among Norplant users who are ovulatory. Serial blood samples were obtained during a 1-month period from women receiving contraceptive service and healthcare at the Center for Research and Services in Human Reproduction and Contraception, Santo Domingo, The Dominican Republic. These women were all sexually active Norplant users who experienced regular menstrual bleeding patterns, and their sequential blood samples were assayed for the presence of human chorionic gonadotropin (hCG) at the Department of Biomedical Sciences at the University of Tampere, Finland. There was also a control group of 20 noncontracepting women included who were trying to conceive. Duration of Norplant was as follows: 4 in the 2nd year of use, 13 in the 3rd year, 11 in the 4th, 3 in the 5th year, and 1 in the 7th year. Pregnancy determination was based on the presence of hCG in the luteal phase by use of a sensitive and specific immunoenzymatic assay that can detect dimeric hCG as early as 7 days postovulation. 9 pregnancies were detected, all in the control group who were trying to conceive. 6 of these advanced to clinical pregnancies and 3 terminated spontaneously at the next menstrual period. None of the Norplant users evidenced and hCG production, whether or not the observed cycles were ovulatory. The probability of finding no pregnancies in the ovulatory months at risk among Norplant users is between 1/50 and 1/150,00. The null hypotheses that Norplant users conceive at a natural rate can be rejected at the 0.05 level. Thus, interruption of early pregnancy (menstrual abortion) does not play a role in the mechanism of action of Norplant contraceptive implants.

Ovulatory dysfunction during continuous administration of low-dose levonorgestrel by subdermal implants.

OBJECTIVE: To study the endocrinologic profile of regularly menstruating users of levonorgestrel subdermal implants. DESIGN: Observational, prospective, case-controlled comparative study. SETTING: The Family Planning Clinic of PROFAMILIA, in Santo Domingo, Dominican Republic. PATIENTS, PARTICIPANTS: Thirty one regularly cycling Norplant users and 12 nonhormonal contraceptors who volunteered to participate. INTERVENTIONS: Norplant contraceptive implants were inserted in 31 subjects between 13 and 77 months before this study. MAIN OUTCOME MEASURES: Follicle-stimulating hormone, luteinizing hormone, estradiol (E2), and progesterone (P) were serially assayed for one menstrual cycle. RESULTS: Almost half of the cycles among Norplant users were anovulatory; all the rest (55%) had some form of dysfunction: diminished gonadotropin surge, luteal phase insufficiency (low P levels and shortened luteal phase), and E2 profiles different from normal controls. CONCLUSIONS: Anovulation is clearly one of the main mechanisms of action of Norplant, but even in presumptive ovulatory cycles, the dysfunctions described possibly contribute to the high contraceptive effectiveness of Norplant.

PIP: The study sought to examine the endocrinologic profile of regularly menstruating users of levonorgestrel subdermal implants. This observational, prospective, case-controlled, comparative study occurred at the Family Planning Clinic of PROFAMILIA in Santo Domingo, Dominican Republic. 31 subjects agreed to receive Norplant contraceptive implants between 13-77 months prior to this study and there were 12 nonhormonal contraceptors who also volunteered to participate. Follicle stimulating hormone, luteinizing hormone, estradiol (E2), and progesterone (P) were serially assayed for 1 menstrual cycle, and almost 1/2 of the cycles of norplant acceptors were anovulatory: the remainder (55%) had some form of dysfunction such as diminished gonadotropin surge, luteal phase insufficiency (low P levels and shortened luteal phase), and E2 profiles different from controls. Anovulation is clearly 1 of the main mechanisms of Norplant action, but even in presumptive ovulatory cycles, the dysfunctions described could have contributed to the high contraceptive effectiveness of Norplant.

The menstrual cycle in women using an intrauterine device.

The duration and hormonal characteristics of the menstrual cycles of women using Copper T intrauterine devices (IUDs) were studied. Daily load samples were obtained during both the pre- and postovulatory phases of 30 IUD-associated cycles and the hormone values were compared with those of 15 normally menstruating women not using contraception. The ovulation rate and peak levels of 17 beta-estradiol and luteinizing hormone (LH) were not significantly different between the two groups. The average number of days from the 1st day of menstrual bleeding to the LH peak (the proliferative phase) was longer in the IUD users. The number of days from the LH peak to the onset of menstrual bleeding (the luteal phase) was shorter in the IUD users. Because of the compensating nature of these statistically significant differences, the total cycle length appeared to be unchanged. At the time of menstruation, the plasma levels of both progesterone and 17 beta-estradiol were significantly higher among IUD users. It is concluded that the presence of an IUD does not influence ovarian function, but that ovarian steroid production and endometrial events become asynchronous.

PIP: The duration and hormonal characteristics of the menstrual cycles of women using the Copper T IUD were studied. Daily blood samples were obtained during the pre- and postovulatory phases of 30 IUD-associated cycles and the hormone values were compared with those of 15 normally menstruating women not using contraception. The ovulation rate and peak levels of 17 beta-estradiol and (LH) luteinizing hormone were not significantly different between the 2 groups. The average number of days from the 1st day of menstrual bleeding to the LH peak (proliferative phase) was longer in IUD users. The number of days from the LH peak to onset of the menstrual bleeding (luteal phase) was shorter in the IUD users. Because of the compensating nature of these statistically significant differences, the total cycle length appeared to be unchanged. At the time of menstruation, the plasma levels of both progesterone and 17 beta-estradiol were significantly higher among IUD users. It is concluded that the presence of an IUD does not influence ovarian function, but the ovarian steroid production and endometrial events do become asynchronous.

Pituitary-ovarian function after tubal ligation.

Pituitary-ovarian function was evaluated by measurement of daily serum levels of luteinizing hormone (LH), 17 beta-estradiol, and progesterone in women with a previous history of tubal ligation. Normally menstruating women served as controls. The duration of the proliferative and luteal phase was similar for both groups. The midluteal progesterone level averages did not differ between the two groups. Preovulatory LH and 17 beta-estradiol peaks were significantly lower in the tubal ligation group; average midluteal LH and 17 beta-estradiol levels were also lower. These results reveal that pituitary-ovarian function can be altered following surgical sterilization.

PIP: Menstrual disorders have been reported following tubal surgery. This study investigates luteinizing hormone (LH), 17beta-estradiol, and progesterone levels in 30 women (age range, 24-38 years; average age, 32 years), who had had elective tubal ligation for fertility control. Elective surgical sterilization was performed between 1 month and 8 years previously. The controls consisted of 15 normally menstruating women (aged 20-32 years; average age, 24), seeking to become pregnant who had not used either oral contraceptives or IUDs for at least 1 month before the study. Daily blood samples were collected starting from day 10 of the menstrual cycle until the onset of the next menstruation. Case selection and specimen collections were done in Santo Domingo, Dominican Republic. Hormone determinations by radioimmunoassays were done on a double-blind basis at the Population Council in New York. Progesterone and 17-b estradiol were determined by radioimmunoassay according to the method of Thorneycroft and Stone, while human luteinizing hormone (hLH) was measured by the double antibody technique of Vaitukaitis et.al. Average duration of the proliferative and luteal phase were 14.4 + or - 3.0 and 13.3 + or - 2.9 days, respectively, for the control group and 13.5 and 2.4 and 14.2 + or - 1.7 days for the women with tubal ligation. The total length of the cycle, 27.7 days, is the same for both groups. The midluteal progesterone level averages did not differ between the 2 groups, although when the controls were compared with tubal ligated women 30 years of age or younger, the difference was significant. Preovulatory LH and 17beta-estradiol peaks were significantly lower in the tubal ligation group, as were the average midluteal LH and 17beta-estradiol levels. These results suggest that surgical sterilization can result in subtle changes in ovarian function, even though ovulation itself is not affected. Bleeding irregularities following tubal ligation may in part be due to the fact that different surgical procedures may have different effects on ovarian blood supply. Further research should be done to compare specific effects of different sterilization procedures on ovarian function.

New insights on the mode of action of intrauterine contraceptive devices in women.

To gain a better understanding of the mechanism of action of intrauterine devices (IUDs), a search was made for ova in the genital tracts of 115 women using no contraception and of 56 women using IUDs, all of whom volunteered for study in conjunction with surgical sterilization. Ova were recovered from tubal flushings between 48 and 120 hours after the midcycle peak of luteinizing hormone in 39% of the IUD users compared with 56% of women in the control group (0.05 less than P less than 0.10). This suggests an action of the IUD before the ovum reaches the uterus. Eggs with a microscopic appearance consistent with fertilization were recovered from the fallopian tubes of half of the women using no contraception who had intercourse within the fertile period of the reproductive cycle and from whom ova were recovered. In contrast (P less than 0.01), no eggs with this appearance were recovered in IUD users who had intercourse within the fertile period. No ova were recovered from the body of the uterus of any of the IUD users. Fertilized ova are less likely to reach the uterine cavity containing an IUD. Thus, the principal mode of IUDs is by a method other than destruction of live embryos.

Delayed first injection of the once-a-month injectable contraceptive containing 25 mg of medroxyprogesterone acetate and 5 mg of E(2)-cypionate: effects on ovarian function.

OBJECTIVE: To assess whether women who were administered the first injection of DMPA+E(2)C on day 7 of their menstrual cycle (delayed injection) exhibit the same degree of ovarian suppression as women who receive it on day 5 of their menstrual cycle. DESIGN: Multicenter, randomized controlled trial. SETTING: Reproductive health clinics. PATIENT(S): Women aged between 18 and 38 years (inclusive) willing to use DMPA+E(2)C as their method of contraception. INTERVENTION(S): Participants received a DMPA+E(2)C injection on day 5 (control group, n = 41) or day 7 (delayed-injection group, n = 117) of their menstrual cycle. MAIN OUTCOME MEASURE(S): Ovarian activity and follicular development determined by serial serum progesterone levels and vaginal ultrasound. RESULT(S): Participants who received DMPA+E(2)C on day 5 of their menstrual cycle (control group) exhibited no more than limited follicular growth (no follicle >16 mm). Of those women who received DMPA+E(2)C on day 7 of their menstrual cycle (delayed-injection group), 21 (18%) showed some follicular growth, of whom 4 (3%) ovulated. CONCLUSION(S): The first injection of DMPA+E(2)C given on day 7 of a menstrual cycle does not provide the same inhibition of ovarian activity as that observed when it is administered on day 5 of the menstrual cycle.

Timing of onset of contraceptive effectiveness in Norplant implant users. Part I. Changes in cervical mucus.

OBJECTIVE: To provide scientific data regarding the changes in cervical mucus within the first hours to days after Norplant implant insertion and to estimate when the cervical mucus is hostile enough to suggest a contraceptive effect. DESIGN: Multicenter, clinical descriptive study. SETTING: Family planning clinics. PATIENT(S): Forty-two women who were between days 8 and 13 of their menstrual cycle and who had requested Norplant implants were admitted to the study. INTERVENTION(S): Cervical mucus and blood samples were obtained. MAIN OUTCOME MEASURE(S): Cervical mucus scores, sperm penetration distances, and serum levels of progesterone, estradiol, and levonorgestrel. RESULT(S): The median cervical mucus score observed at baseline was 6 ("fair"), indicating that the mucus was already somewhat hostile before insertion of the Norplant implants. The median scores declined to 5 at 12 and 24 hours and continued to decrease through day 7 to 2 ("poor"), a score that is judged as hostile to sperm penetration. Overall, 73% of all subjects had a poor cervical mucus score by 3 days after insertion; at 7 days after insertion, 90% exhibited poor mucus and none had a good score. There was a substantial drop in the overall median distance traveled by the vanguard sperm after 12 hours for each cervical mucus score grouping. The distance traveled decreased rapidly between 12 and 24 hours to < 0.5 cm in subjects with fair and poor mucus, and by day 3, 91% of the subjects exhibited poor sperm penetration. CONCLUSION(S): On the basis of our findings, deterioration of the quality of the cervical mucus and sperm penetration is evident by 24 hours after insertion, although not to a level that would suggest adequate protection until 72 hours after insertion. Therefore, we are confident in recommending that backup methods of contraception (e.g, condoms) need not be used for more than 3 days after insertion, even when the implants are inserted close to ovulation. These findings provide policy makers, clinic managers, and clinicians with important information about how they can improve client access to Norplant implants.

PIP: To provide clinicians with evidence as to when the cervical mucus is hostile enough in new Norplant implant acceptors to indicate a contraceptive effect, 42 women requesting Norplant from clinical sites in Santo Domingo, Dominican Republic, and Baltimore, Maryland (US), in 1994-95 were enrolled in a clinical descriptive study. At baseline, when all women were between days 8 and 13 of their menstrual cycle, the median cervical mucus score was 6 ("fair") out of a possible maximum of 12. This score declined to 5 at 12 and 24 hours and continued to decrease through day 7, when it reached 2--a level judged hostile to sperm penetration. Overall, 73% of women had a "poor" cervical mucus score by day 3 and 90% were in this category by day 7. There were substantial drops in the overall median distance travelled by the vanguard sperm and in the percentage of subjects demonstrating poor sperm penetration after 12 hours for each cervical mucus score grouping. 91% of women had poor sperm penetration by day 3 and 93% by day 7. These findings suggest that backup contraceptive protection for the entire cycle after Norplant insertion--a standard recommendation--is not necessary given the profound effect of levonorgestrel on cervical mucus shortly after insertion, even in the event of possible ovulation.

Progestin-only contraceptive rings.

Several progestin-only long acting contraceptives are currently available in the form of implants or injectables. Vaginal rings are another contraceptive option in the final stages of development. These steroid-containing polymer rings are placed in the vagina, providing relatively constant drug release, thus allowing for lower effective doses. Vaginal rings have the advantage of being user-controlled and non-provider dependent, and their use is non-coital related. The first clinical study with medroxyprogesterone acetate vaginal rings was published in 1970. Since then numerous clinical trials testing different steroids and doses have followed. A large Phase III multicenter clinical trial with a levonorgestrel ring, releasing 20 microg/day, was coordinated and sponsored by WHO. The cumulative one-year pregnancy rate was 4. 5%. The principal reasons for discontinuation were menstrual disturbances (17.2%), followed by frequent expulsion of the ring (7. 1%), and vaginal symptoms (6.0%). The finding of erythematous lesions in the vagina in some women has led to the development of a more flexible device. Collaboration with industry should facilitate the manufacture of a redesigned levonorgestrel ring with a higher release rate. The Population Council is also developing a vaginal ring containing Nestorone for 6 months of continuous use. Ovulation inhibition was achieved in over 97% of the segments studied, with rings releasing either 50, 75, or 100 microg/day. No pregnancies occurred in women using the low-dose ring, while one pregnancy each occurred in the intermediate- and high-dose ring groups for a 6-month cumulative pregnancy rate of 0.0, 1.9, and 2.1%. Bleeding irregularities were common. Nestorone is orally inactive; therefore this ring is also excellent for use in lactating women.

Risk-benefit effects of implantable contraceptives in women.

Contraceptive implant technology has been used by millions of women throughout the world. The three marketed implant systems today are levonorgestrel-releasing implants: Norplant and Jadelle, and a single etonogestrel-releasing implant, Implanon. The main benefits common to these delivery systems are their safety, high effectiveness, ease of use, long duration of action (3 - 5 years) and reversibility. Bleeding disturbances are the main adverse events associated with implantable contraceptives. Other minor risks relate to the insertion and removal procedures, which require adequately trained providers as well as aseptic techniques. Furthermore, since initiation and discontinuation of use is provider-dependent and not controlled by the user, there may be a risk of coercion of use on the one hand or, on the other hand, difficulty in access to initiating use, if trained providers are not readily available. Although no single contraceptive method is perfect or appealing to all, contraceptive implants are safe and fulfil a very important need among fertility regulation methods.

Estradiol delivery by vaginal rings: potential for hormone replacement therapy.

OBJECTIVES: To determine if delivery of estradiol from elastomeric vaginal rings gives estradiol blood levels in the range associated with effective estrogen replacement therapy and to determine the relation between in vitro estradiol release from the rings and blood levels in vivo. Secondary objectives related to changes in lipoprotein cholesterol, changes in climacteric symptoms, and evaluation of acceptability to users. METHODS: Three ring variants releasing approximately 100, 150 and 200 micrograms/day of estradiol in vitro were used through 22 days in 21 postmenopausal women, 7 on each dose levels. Blood samples for measurement of estradiol were taken at 3-4 day intervals. Lipoprotein cholesterol was measured before and at the end of treatment. Women were questioned about climacteric symptoms and about their satisfaction with the ring. RESULTS: Mean serum estradiol levels for the three groups of rings were 63 +/- 6, 94 +/- 5 and 136 +/- 13 pg/ml for the 100, 150 and 200 micrograms/day rings, respectively. FSH levels declined during ring use and the maturation values of cells collected on vaginal swabs markedly increased. Total and LDL cholesterol were significantly reduced and HDL cholesterol was not significantly changed. All women reported relief of postmenopausal symptoms. Vaginal discomfort during the first 3 days of use was reported by 12 women but overall satisfaction with the method was high. CONCLUSIONS: Women using the vaginal rings attained estradiol blood levels compatible with control of climacteric symptoms and bone loss. The relation between in vitro estradiol release and blood levels in vivo was essentially identical for all 3 doses. The use of vaginal rings to deliver estradiol for hormone replacement therapy is judged to merit further evaluation.

Anovulation, inadequate luteal phase and poor sperm penetration in cervical mucus during prolonged use of Norplant implants.

Blood samples for progesterone assay were collected for a total of 49 cycles, from 27 volunteers using the NORPLANT system. Levonorgestrel determinations were carried out in the same samples. A group of 12 women with normal cycles were studied in the same manner to serve as controls. Of the 49 cycles studied, 20 (41%) were ovulatory. The mean levonorgestrel level in ovulatory patients was 0.34 +/- 0.11 ng/ml (S.D.) compared to 0.42 +/- 0.14 ng/ml (S.D.) in anovulatory cycles. Compared to the control group, progesterone levels were significantly lower for users of NORPLANT implants during days -12 to -10 (p less than 0.025), -9 to -7 (p less than 0.05), -6 to -4 (p less than 0.0005) and days -3 to -1 (p less than 0.01). Cervical mucus evaluations and post-coital tests were done around mid-cycle in 29 of the cycles studied. All samples of cervical mucus were of poor quality, viscous and scarce, with a mean SPK of 4.1 +/- 2.3 cm. Most had absent or atypical ferning. Twenty-one subjects (73%) had a post-coital score of 1, and 4 (14%) of zero. Thus, anovulation, inadequate luteal phase and the direct effect of the continuous administration of levonorgestrel over cervical function, all seem to contribute to the effectiveness of NORPLANT implants.

Nonmenstrual adverse events during use of implantable contraceptives for women: data from clinical trials.

Contraceptive methods, including implants, do not prevent common symptoms and adverse health events that most people experience. It is difficult, therefore, to decide whether or not the occurrence of symptoms or adverse events that are common can be attributed to use of a contraceptive method or to determine if a given method changes the likelihood of their occurrence. Based on the review of the literature, no apparent differences in the frequency of adverse events are evident between the six-implant or two-rod levonorgestrel systems and the single implant etonogestrel and nomegestrol acetate systems. The most frequent adverse events reported in clinical trials that are probably related to implant use are headaches and acne. Weight gain, dizziness, and mood changes are also frequently mentioned adverse events and are possibly steroid-related. Other possibly related adverse events, although much less frequently reported, are loss of libido, fatigue, hair loss, and other skin conditions. Persistent ovarian follicles that spontaneously disappear are a common event during use of progestin-only contraceptives, and providers should be aware of this condition to avoid unnecessary interventions. Overall, the vast experience reported in the clinical studies reviewed here show that all existing implantable contraceptives are equally safe. This can probably be attributed to the low-hormonal dose delivered by progestin-implant systems.