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.

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.

Does meloxicam increase the incidence of anovulation induced by single administration of levonorgestrel in emergency contraception? A pilot study.

BACKGROUND: Levonorgestrel (LNG) consistently prevents follicular rupture only when it is given before the onset of the ovulatory stimulus. As locally synthesized prostaglandin (PG) plays a crucial role in follicular rupture and cyclooxygenase-2 (cox-2) catalyses the final step of PG synthesis, we reasoned that adding a cox-2 inhibitor to LNG would prevent follicular rupture even after the ovulatory process had been triggered by the gonadotrophin surge. METHODS: Forty-one women were divided into two groups. One was treated when the size of the leading follicle was 15-17 mm (n=10) and the other when it was >or=18 mm (n=31). Each woman contributed with one cycle treated with LNG 1.5 mg single dose plus placebo and another treated with LNG + meloxicam (Melox) 15 mg, in a randomized order. Serial blood sampling for the assay of LH and follicular monitoring by transvaginal ultrasound were performed before and after treatment. RESULTS: Follicular rupture failed to occur within the 5-day period that followed treatment in 50 and 70% of cycles treated with LNG + Placebo and LNG + Melox, respectively, in the 15-17 mm group (P=0.15) and in 16 and 39% of cycles treated with LNG + Placebo and LNG + Melox, respectively, in the >or=18 mm group (P < 0.052). The overall proportion of cycles with no follicular rupture or ovulatory dysfunction increased significantly by the addition of Melox to LNG (66 versus 88%, P < 0.012; n=41-matched pairs). CONCLUSIONS: The trend towards increased incidence of no follicular rupture when Melox was combined with LNG suggests that the addition of a cox-2 inhibitor has the potential to improve the contraceptive efficacy of LNG by a pre-fertilization effect.

Pituitary-ovarian function following the standard levonorgestrel emergency contraceptive dose or a single 0.75-mg dose given on the days preceding ovulation.

We assessed to what extent the standard dose of levonorgestrel (LNG), used for emergency contraception, or a single dose (half dose), given in the follicular phase, affects the ovulatory process during the ensuing 5-day period. Fifty-eight women were divided into three groups according to timing of treatment. Each woman contributed with three treatment cycles separated by resting cycles. All received placebo in one cycle, and standard or single dose in two other cycles, in a randomized order. The diameter of the dominant follicle determined the time of treatment. Each woman had the same diameter assigned for all her treatments. Diameters were grouped into 33 categories: 12-14, 15-17 or 18-20 mm. Follicular rupture failed to occur during the 5-day period in 44%, 50% and 36% of cycles with the standard, half dose and placebo, respectively. Ovulatory dysfunction, characterized by follicular rupture associated with absent, blunted or mistimed gonadotropin surge, occurred in 35%, 36% and 5% of standard, single dose or placebo cycles, respectively. In conclusion, LNG can disrupt the ovulatory process in 93% of cycles treated when the diameter of the dominant follicle is between 12 and 17 mm. It is highly probable that this mode of action fully accounts for the contraceptive efficacy as well as the failure rate of this method. The present data suggest that half the dose may be as effective as the standard dose.

Emergency contraception--clinical and ethical aspects.

Emergency contraception (EC) consists of either 1.5 mg of levonorgestrel (LNG) in one or two doses, or a combination of LNG with ethinylestradiol, administered for up to 5 days after unprotected intercourse. Clinical studies indicate that LNG alone is more effective and has less side effects. Its effectiveness decreases the longer after coitus it is taken. EC is indicated when there is non-compliance or accidents with the use of regular methods of contraception, or when women have had voluntary or imposed unprotected intercourse. The ethics of providing EC has been questioned by some, arguing that it acts by preventing implantation. Scientific evidence does not support this concept, but shows that EC acts mostly before fertilization. Placing obstacles to the access of EC is unethical as it transgresses the ethical principles of autonomy, non-maleficence beneficence and justice. Far from inducing abortions, EC reduces unwanted pregnancies and prevents abortion.

Local side effects observed among long-term users of norplant contraceptive implants.

The prevalence of local signs and symptoms related to the site of insertion of implants, and the association of these signs and symptoms with time of use, skin color and body mass index (BMI) was evaluated among users of the Norplant implant system. Three hundred and three Norplant users attending at the reproductive health clinic of PROFAMILIA in Santo Domingo, Dominican Republic, were asked if they had ever had any discomfort at the site/arm of implant insertion and the implant insertion area was examined and hyperpigmentation and hollowing of the surface was recorded. Half of the subjects reported either pain or paresthesia or both, in almost equal numbers, some time since insertion. Hyperpigmentation was observed in 35.6% and hollowing in 22.4% of the subjects. Report of pain and paresthesia was inversely associated to time of use and to BMI. Hyperpigmentation was directly associated to time of use and darker skin, and hollowing of the arm surface in the implants area with time of use and BMI. Local signs and symptoms were more frequent than previously reported, although they were of mild nature and appeared not to worry most of the users.

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.

Effects of the Yuzpe regimen, given during the follicular phase, on ovarian function.

This study was conducted to assess to what extent the Yuzpe regimen, or half the dose, given in the follicular phase, prevents ovulation during the ensuing 5 days. Sixty women were divided into six groups. All groups received placebo in one cycle and drug in another, in a randomized order. Groups differed by the dose and size of the leading follicle at the time of treatment (12-14, 15-17, or 18-20 mm). Ovulation was absent during the ensuing 5 days in 13 of 20 participants (65%) and in 8 of 20 participants (40%) who received the full and the half dose, respectively, when follicles were 12-17 mm. No ovulation occurred, within the critical period, in 7 of 39 placebo cycles (18%). When follicles were 18-20 mm, treatment did not prevent ovulation. In most drug-treated cycles, plasma gonadotropin and sex steroid levels were significantly depressed within the 5-day period, even when follicular rupture occurred within that period. In conclusion, the Yuzpe regimen can suppress or postpone ovulation to an extent that exceeds the fertile life of spermatozoa. Lack of ovulation within the critical period and dysfunction of the ovulatory process probably account for the contraceptive effect of this method in most cases. The present data do not warrant the use of half the dose of the Yuzpe regimen.

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.

Levonorgestrel concentrations during 7 years of continuous use of Jadelle contraceptive implants.

Serum levonorgestrel concentrations were assayed in a multicenter, 7-year study of 199 users of Jadelle rod implants. We examined drug levels, patterns of changes, factors affecting drug levels, and concentrations at which pregnancies occurred. Mean levonorgestrel concentrations declined from 435 pg/mL at 1 month of use to 64% of that value (280 pg/mL) at the end of 3 years. Between the end of the third and fifth years neither mean nor median serum levels varied markedly. At 5 years the mean concentration was again 64% of the first month's mean. Declining levels were observed thereafter through the end of 7 years when the mean, 224 pg/mL, was 52% of the 1-month value. Last measured drug concentrations of women who became pregnant during Jadelle use had mean and median values of 152 and 144 pg/mL, respectively, and a maximum value of 180 pg/mL. Analyses indicated ponderal index, body weight, duration of use, and a single clinical center were the most important variables affecting measured levonorgestrel levels. Approximately one-third of assays in the sixth and seventh years were found to be below 180 pg/mL, suggesting that Jadelle levonorgestrel implants would not maintain sufficiently high levels of effectiveness against pregnancy after 5 years and that heavier women would then be at greater risk of pregnancy.

Ovarian function during use of vaginal rings delivering three different doses of Nestorone.

Contraceptive vaginal rings delivering various progestins alone or in combination with estrogen have been previously studied, showing adequate steroid vaginal absorption and acceptability by the users. Nestorone progestin (NES) is a potent 19-nor-progesterone derivative, inactive by the oral route, but an excellent option for vaginal delivery. The purpose of this study was to evaluate ovarian function during 6 months of continuous use of progestin-only vaginal rings delivering 3 different doses of NES: 50, 75, and 100 microg per day. Blood samples were taken twice a week for 5 consecutive weeks during a control cycle and on months 1, 3 and 6 of use, for the measurement of estradiol (E2), progesterone (P), and NES. A total of 87 volunteers randomly received each of the 3 doses. After an initial peak, NES serum levels remained fairly constant throughout the duration of the study at about 125, 200 and 250 pmol/L, respectively, decreasing slightly with time. Luteal activity occurred very rarely (1.2-2.6% of sampling periods) with no apparent difference between doses. Low E2 levels (< or =100 pmol/L) in all samples of a run were rare (5%) and only with the high dose ring (100 microg/day). E2 remained within normal levels (101-1500 pmol/L) in most of the segments studied. We conclude that the 50 and 75 microg/day NES rings provide adequate ovulation inhibition without hypoestrogenism, while the 100 microg/day ring may deliver an unnecessarily high dose.

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.

Delayed first injection of the once-a-month injectable contraceptive containing 25 mg medroxyprogesterone acetate and 5 mg estradiol-cypionate: effects on cervical mucus.

The objectives of this study were to assess whether women who were administered the first injection of the once-a-month contraceptive containing estradiol cypionate and 25 mg depot-medroxyprogesterone acetate (MPA+E(2)C) on Day 7 of their menstrual cycle (delayed injection) exhibit the same degree of cervical mucus changes as women who receive it on Day 5 of their menstrual cycle. This was a multicenter, randomized, controlled clinical trial. A total of 158 women, aged between 18 and 38 years (inclusive), who, were willing to use MPA+E(2)C as their contraceptive method participated in the trial. Participants received a MPA+E(2)C injection on Day 5 (control group, n = 41) or Day 7 (delayed-injection group, n = 117) of their menstrual cycle. Participants who received MPA+E(2)C on Day 5 of their menstrual cycle (control group) exhibited fair or poor mucus quality and poor sperm penetration. Of those women who received MPA+E(2)C on Day 7 of their menstrual cycle (delayed-injection group), 3 (3%) showed good mucus or good sperm penetration at some time point during follow-up. It is possible to conclude that the first injection of MPA+E(2)C given on Day 7 of a menstrual cycle does not provide the same degree of inhibition of mucus quality and sperm penetration as that observed if it is administered on Day 5. However, the theoretical risk of pregnancy after receiving MPA+E(2)C on Day 7 would be expected to be low.

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.

Prolonged effectiveness of Norplant(R) capsule implants: a 7-year study.

Soft tubing Norplant(R) contraceptive implants were studied in 1210 women for 7 years to measure the duration of effectiveness and the magnitude of the pregnancy rates over that time. Mean age at enrollment was 27.4 years. Of the enrollees, 42% were US residents. One-sixth (16.1%) weighed >/=70 kg at the time of implant placement. At the end of 5 years, the cumulative pregnancy rate was 1.1/100; at the end of 7 years, it was 1.9/100. No pregnancies occurred to any of the 400 women who enrolled in the study at age >/=30 years and who weighed <100 kg. Among women aged 18-33 years, the 7-year Norplant pregnancy rates are comparable to the median pregnancy rates of tubal sterilization methods for women of the same age and duration of use. For women aged >/=34 years, without regard to weight at admission, the 7-year effectiveness of soft tubing Norplant equals or surpasses that of tubal sterilization. For continuing implant users, annual pregnancy rates <1.0/100 in years 6 and 7, together with low cumulative pregnancy rates, testify that Norplant capsule implants remain highly effective for 7 years.

Ovarian function during use of Nestorone(R) subdermal implants.

Nestorone(R) progestin (NES) is a potent 19-nor-progesterone derivative which is biologically inactive when administered orally; however, it is an excellent option for implant contraception. The objective of this study was to evaluate ovarian function during use of either one 4-cm or two 3-cm NES implants for 24 months. A total of 60 volunteers were enrolled in each dose group. Vaginal ultrasound (VUS) and blood sampling for determinations of estradiol (E(2)), progesterone (P) and NES serum levels were carried out twice a week for 6 consecutive weeks, beginning in months 1, 6, 12, 18, and 24 of implant use. Serum levels of NES declined with time, with a more pronounced decrease during the first 18 months of implant use; thereafter, NES levels remained stable until the end of the study at 24 months. Luteal activity was very infrequent during the first year of use (<3%) but increased during the second year, occurring in 27% and 35% of the sampling periods in the 1-implant group, and 2% and 16% of the sampling periods in the 2-implant group, at months 18 and 24 of use, respectively. No luteal activity was observed with NES levels above 80 pmol/L. Serum P levels in periods of luteal activity were significantly lower than those of controls. Persistent anovulatory follicles were the most common VUS finding and this was associated with E(2) levels that remained within the normal range (101-1500 pmol/L) in the majority of the sampling periods studied. Considering that a single implant offers advantage for insertion and removal, a new single NES implant is being developed with a slightly higher release rate, to reduce effectively the incidence of ovulation and provide a greater margin of safety beyond 2 years.

Vaginal epithelial surface appearances in women using vaginal rings for contraception.

Vaginal inspections using colposcopy before insertion of contraceptive vaginal rings and at 2-month intervals during ring use were conducted on 169 users of four different formulations. The rings studied released Nestorone alone (50, 75, 100 g daily over 6 months); ethinyl estradiol: Nestorone (30:100 and 15:150 g daily over 6 months); ethinylestradiol:norethindrone acetate (20:1000 and 15:1000 g daily over 4 months); and ethinyl estradiol:norethindrone acetate (20:1000 g daily over 12 months). A total of 88 altered or atypical conditions of the vaginal surface appearance were recorded in 507 inspections (17.4% of inspections). Many of these atypical appearances were quite subtle. The incidence was significantly higher (p <0.01) than in the single pretreatment examinations (11 in 158 inspections; 7.0%), but closely matched that of a "control group" of sexually active women who were the subject of an earlier study by the same investigators. In that study, the incidence was 18% (57 atypical conditions in 317 inspections). In all, 83% of atypical conditions identified in the vagina during ring use had disappeared by the next scheduled colposcopy despite continued ring use. Findings of potential significance were conservatively defined as all ulcerations, those abrasions and ecchymoses that were >0.5 cm in any direction, and fields of five or more petechiae. Findings fitting those criteria comprised 30% of atypical conditions in ring users, 33% in the control group, and 27% pretreatment. The corresponding incidence as a percentage of inspections were 5.3%, 6. 0%, and 2.5% in the ring users, control groups, and pretreatment groups, respectively. These differences were not statistically significant. The findings suggest that the vaginal rings included in the studies contributed little, if at all, to clinically significant lesions or to total lesion incidence. Further definition would require a larger and longer-term study with matched controls.

Prevalence of enlarged ovarian follicles among users of levonorgestrel subdermal contraceptive implants (Norplant).

OBJECTIVE: The aim of this study was to determine the prevalence of enlarged follicles, as detected by a single clinical or ultrasonographic examination, among users of levonorgestrel subdermal contraceptive implants (Norplant implants). STUDY DESIGN: This was a cross-sectional study of 103 users of Norplant implants and 50 users of the TCu380A intrauterine contraceptive device, all of whom received reproductive health services from PROFAMILIA, Santo Domingo, Dominican Republic. Bimanual pelvic examination and vaginal ultrasonography were performed. Enlarged follicles (>25 mm) were followed up weekly. The chi(2) test was applied to these data. RESULTS: Enlarged follicles were detected by ultrasonography in 17. 5% of Norplant implants users and 4% of TCu380A intrauterine contraceptive device users, respectively (P <.04). There was no difference according to duration of use. The longest time to involution of the follicles was 4 weeks. Forty percent of the enlarged follicles detected by ultrasonography were also detected by bimanual pelvic examination. CONCLUSION: Enlarged follicles are a frequent finding among women who use Norplant implants, but they are less frequent than described in previous studies, which were based on serial ultrasonographic scans in selected groups of users. Physicians and users should be aware of the transient nature of these enlarged follicles, which do not require intervention.