Search

Objective: The safety and tolerability of a new low-dose levonorgestrel/ethinyl estradiol (LNG/EE) contraceptive patch was compared with 2 combination oral contraceptives in 2 clinical studies in which approximately 30% of enrolled participants were obese., Study Design: Two phase 3, open-label, randomized, parallel-group, multicenter trials compared the LNG/EE contraceptive patch (n = 1579) with combination oral contraceptives (n = 581) in healthy women 17-40 years of age. Combination oral contraceptives were LNG 100 μg per EE 20 μg (combination oral contraceptive 20; n = 375) or LNG 150 μg per EE 30 μg (combination oral contraceptive 30; n = 206). Safety and tolerability data from the 2 trials were evaluated in integrated safety analyses., Results: Treatment-emergent adverse events of 2% or greater in the LNG/EE contraceptive patch were nasopharyngitis (5.2%), nausea (4.1%), upper respiratory infection (3.5%), headache (3.4%), sinusitis (2.9%), cervical dysplasia (2.3%), and urinary tract infection (2.1%). Including skin reaction-related treatment-emergent adverse events, the proportion of women who experienced any treatment-emergent adverse event was similar among women randomized to the contraceptive patch (47.5%), the combination oral contraceptive 20 (47.4%), or the combination oral contraceptive 30 (46.8%). The incidence of treatment-emergent adverse events was similar in obese vs nonobese participants in all groups. Serious adverse events occurred in less than 1% of participants in any of the treatment groups., Conclusion: The LNG/EE contraceptive patch and combination oral contraceptives were well tolerated and associated with similar treatment-emergent adverse event incidences in obese and nonobese women., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: To evaluate skin irritation and patch adhesiveness of a new weekly low-dose levonorgestrel (LNG) and ethinyl estradiol (EE) contraceptive patch (LNG/EE patch)., Study Design: This analysis was part of an open-label, parallel-group, multicenter, phase 3 study that randomized healthy women to the LNG/EE patch (one patch weekly for three consecutive weeks, followed by a patch-free week for 13 cycles) or to an oral contraceptive for six cycles followed by seven LNG/EE patch cycles. Participants selected patch application sites of abdomen, buttock or upper torso. Investigators rated patch adhesiveness and skin irritation using standardized scales. Participants rated skin irritation and itching daily using standardized scales and recorded patch fall-off on daily diary cards., Results: A total of 32,508 patches were applied (n=1273). At the five clinic visits in which investigators rated the patches, they rated adhesiveness=0 (no lift) for ≥84% of participants and skin irritation=absent/mild for 97% of patches. Participants reported that 2-3.7% of patches fell off and rated skin irritation as absent or mild for 92- 95% of patches, according to site., Conclusion: Investigator- and participant-rated assessments of LNG/EE patch adhesiveness and irritation demonstrated a low incidence of patch detachment, skin irritation and pruritus., Implications Statement: This secondary analysis of a phase 3 clinical trial of a new weekly low-dose LNG and EE contraceptive patch, which used assessment by both investigators and participants, observed a low incidence of skin irritation, pruritus and patch detachment., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: Pregnancy rates in US contraceptive clinical trials are increasing due to decreased treatment compliance. This study compared compliance with a new low-dose levonorgestrel (LNG) and ethinyl estradiol (EE) contraceptive patch (CP, Twirla™) with that of a low-dose combination oral contraceptive (COC) in a demographically diverse population., Study Design: This analysis was part of an open-label, parallel-group, multicenter phase 3 study that randomized healthy sexually active women (17-40years) to 13cycles of LNG/EE CP or 6cycles of COC, then 7cycles of LNG/EE CP. We defined self-reported compliance as cycles that, according to diaries, show 21days of patch wear without missed days or any patch worn >7days or 21days of pill-taking without missed pill days. We verified compliance by detectable plasma presence of LNG and EE at cycles 2, 6, and 13., Results: Of the intention-to-treat population with diary information (N=1328, mean age 26.4years, 46% minorities, 33% obese), 10.0% of the CP (n=998) versus 21.2% of the COC group (n=330) self-reported noncompliance after 6cycles (p<.001). Laboratory assessments verified 10-14% of participants in both groups as noncompliant. Self-reported perfect use did not vary between obese [body mass index (BMI) ≥30kg/m(2)] versus nonobese (BMI <30kg/m(2)) participants in both groups or when stratified by age, education, or race/ethnicity in the CP group., Conclusions: Self-reported compliance was significantly greater in the CP than COC group and did not vary by obesity status. Discrepancies between self-reported and verified compliance question reliability of patient diaries., Implications Statement: This paper, based on an analysis of a phase 3 trial, shows that compliance was significantly greater with a new weekly transdermal CP than with a once-daily COC in obese as well as nonobese participants. Discrepancies between self-reported compliance and laboratory-verified compliance raise questions regarding the reliability of patient diaries., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: The metabolic effects of progestin-only long-acting reversible contraception [levonorgestrel-releasing intrauterine system (LNG-IUS) and etonogestrel implant (ENG-I)] have been studied in normal-weight women but not in obese [body mass index≥30kg/m(2)] women., Study Design: A nonrandomized open-label prospective trial of healthy obese, reproductive-age women desiring to use long-acting reversible contraception (LARC) or nonhormonal contraception (NHC). At baseline, 3 months and 6 months, homeostasis model assessment insulin resistant (HOMA-IR) score, insulin sensitivity (HOMA-%S) and β-cell function (HOMA-%B) were calculated based on fasting insulin and glucose values. In addition, components of metabolic syndrome [fasting glucose (FG), high density lipoprotein cholesterol and triglycerides, systolic and diastolic blood pressure, abdominal circumference] were measured. Twenty-four subjects total (8 in each arm) were needed to detect a 1.0 difference in HOMA-IR with 80% power and a two-sided alpha of 0.05., Results: We present data on eight NHC, eight ENG-I and nine levonorgestrel intrauterine system (LNG-IUS) users. FG increased, and insulin sensitivity decreased over time among ENG-I users to a greater extent than among LNG-IUS users when compared to women using a nonhormonal method [FG change over 6 months=9.4mg/dL, 4.6mg/dL and -2.1mg/dL, respectively; p=.01); (HOMA-%S change over 6 months=-29.9%, -14.8% and 19.3%, respectively; p=.02)], while β-cell function and insulin resistance did not change significantly (p>.05)., Conclusion: While changes in FG and insulin sensitivity were seen in the present study among obese progestin-only contraceptive users, either progestin-only LARC method may be safely used clinically., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: This study analyzes levels of progesterone, estradiol, norethindrone (NET) and ethinyl estradiol (EE) in serum and levels of NET in cervical mucus on the last day of the hormone-free interval (HFI) in users of 24/4 [norethindrone acetate (NETA)/EE-24] vs. 21/7 (NETA/EE-21) regimens., Study Design: This was a randomized controlled, crossover, equivalency trial. Subjects were randomized to receive NETA/EE-24 or NETA/EE-21 for 2 months and then switched between study drugs. Blood and cervical mucus samples were obtained on Days 12-16 and on the last day of the HFI., Results: From April 2010 to November 2011, 32 subjects were enrolled with 18 subjects completing all study visits. There were no statistically significant differences in either day 12-16 (p=.54) or last hormone-free day (p=.33) cervical mucus NET concentrations between the regimens. On the last day of the HFI, median serum progesterone levels did not differ significantly; however, users of NETA/EE-24 had higher levels of serum NET (p<.001) and users of NETA/EE-21 had higher levels of serum estradiol (p=.01)., Conclusion: This data supports the fact that inhibition of the pituitary-ovarian axis occurs during oral contraceptive use and during the HFI. We demonstrated that a reduced HFI of 4 days resulted in better suppression of the ovarian hormone production, thereby reducing the risk of ovulation and potential contraceptive failure., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: The major contraceptive action of the levonorgestrel-releasing intrauterine system (LNG-IUS) is cervical mucus (CM) thickening, which prevents sperm penetration. No study to date has examined the temporal relationship between the insertion of the LNG-IUS and changes in CM quality and sperm penetration., Study Design: Participants were enrolled in a clinically descriptive study to compare the quality of CM and three parameters of sperm penetration prior to insertion of the LNG-IUS and on Days 1, 3 and 5 after insertion. Measurements of estradiol, progesterone and levonorgestrel (LNG) in serum and LNG in CM were also carried out at these times. CM was analyzed using the World Health Organization CM grading criteria. Sperm penetration was determined using an in vitro sperm-CM penetration test., Results: All 10 participants underwent LNG-IUS insertion during midcycle when CM quality was good and sperm penetration was excellent. On Day 1 after LNG-IUS insertion, the majority of participants demonstrated poor CM quality and poor sperm penetration. On Day 3, all participants had poor CM quality, and all but one subject had poor sperm penetration. By Day 5, all participants had poor CM quality and poor sperm penetration. LNG levels in CM peaked on the day after LNG-IUS insertion., Conclusion: Significant changes in quality of CM and sperm penetration were observed shortly after LNG-IUS insertion; however, CM can remain penetrable for up to 5 days when the LNG-IUS is inserted midcycle., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Steady progress in contraception research has been achieved over the past 50 years. Hormonal and nonhormonal modern contraceptives have improved women's lives by reducing different health conditions that contributed to considerable morbidity. However, the contraceptives available today are not suitable to all users, and the need to expand contraceptive choices still exists. Novel products such as new implants, contraceptive vaginal rings, transdermal patches and newer combinations of oral contraceptives have recently been introduced in family planning programs, and hormonal contraception is widely used for spacing and limiting births. Concerns over the adverse effects of hormonal contraceptives have led to research and development of new combinations with improved metabolic profile. Recent developments include use of natural compounds such as estradiol and estradiol valerate with the hope to decrease thrombotic risk, in combination with newer progestins derived from the progesterone structure or from spirolactone, in order to avoid the androgenic effects. Progesterone antagonists and progesterone receptor modulators are highly effective in blocking ovulation and preventing follicular rupture and are undergoing investigations in the form of oral pills and in semi-long-acting delivery systems. Future developments also include the combination of a contraceptive with an antiretroviral agent for dual contraception and protection against sexually transmitted diseases, to be used before intercourse or on demand, as well as for continuous use in dual-protection rings. Although clinical trials of male contraception have reflected promising results, limited involvement of industry in that area of research has decreased the likelihood of having a male method available in the current decade. Development of nonhormonal methods is still at an early stage of research, with the identification of specific targets within the reproductive system in ovaries and testes, as well as interactions between spermatozoa and ova. It is hoped that the introduction of new methods with additional health benefits would help women and couples with unmet needs to obtain access to a wider range of contraceptives with improved acceptability., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: The effect of obesity on ovarian follicular suppression in women using low-estrogen dose contraceptive patches has not been determined., Study Design: A Phase II, parallel-group, multicenter, three-cycle study evaluated three patches containing different ethinyl estradiol (EE) and levonorgestrel (LNG) doses. Serum levels of EE, LNG, sex hormone-binding globulin and progesterone were compared in 41 obese [body mass index (BMI) ≥30] and 75 nonobese (BMI <30) women., Results: Suppression of ovulation during the luteal phase was dose dependent, with the highest dose (AG200-15) preventing progesterone increases in all women (cycles 2-3). In the follicular phase, the lowest-dose patch had the highest rate of increased progesterone in nonobese subjects. Progesterone levels ≥3.0 ng/mL in the follicular phase were more common in obese than nonobese women., Conclusions: AG200-15 suppresses ovulation in obese and nonobese women. All three patches found increased progesterone in the follicular phase, albeit more in obese versus nonobese women., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Few studies have examined the action of combined oral contraceptives (COCs) on cervical mucus. We hypothesized that midcycle cervical mucus of women taking COCs is of poor quality when compared to their own midcycle mucus prior to initiating COCs. We sought to compare the effect upon quality and sperm penetration of the cervical mucus on the last hormone-free day with a 24/4 regimen to a 21/7 regimen., Methods: This is an open-label, investigator-blinded, randomized, controlled, crossover equivalency study. All subjects received, in random order, 2 months of a 21/7 regimen and 2 months of a 24/4 regimen, each containing 20 mcg ethinyl estradiol and 1 mg norethindrone acetate. Analysis of cervical mucus quality (CMQ) and sperm penetration took place midcycle and on the last day of the hormone-free interval during the second month of each COC treatment., Results: From April 2010 to November 2011, 18 subjects completed all study visits. Mean midcycle CMQ was poor (mean CMQ=1) and did not differ between 24/4 and 21/7 regimens (p=.92). On the last day of the pill-free interval, the quality and sperm penetration were poor with both regimens., Conclusion: This study indicates that thickening of cervical mucus is a major mechanism of contraceptive action of COCs and that both 21/7 and 24/4 regimens result in poor quality and impenetrable mucus on the last day of the pill-free interval., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Subcutaneous depo-medroxyprogesterone acetate (DMPA-SC) has not been studied in the extremely obese population (BMI >or=40 kg/m(2)). The purpose of this 26-week prospective experimental study was to determine incidence of ovulation and follicular development among women with Class 1, 2 and 3 obesity after receiving DMPA-SC., Methods: Five normal-weight, five Class 1-2 obese, and five Class 3 obese women received subcutaneous injections of 104 mg DMPA-SC at baseline and 12 weeks later. Weekly progesterone levels, bimonthly estradiol (E(2)), and monthly medroxyprogesterone acetate (MPA) levels were measured by immunoassay methods for a total of 26 weeks in each subject., Results: Ovulation did not occur in any subject more than 1 week after the first injection. There was large intersubject and intrasubject variability in E(2) levels, and fluctuating E(2) levels were more frequent among obese women than normal-weight women. Median MPA levels remained above the level needed to prevent ovulation but, compared with normal-weight subjects, were lower among Class 1-2 obese and lowest among Class 3 obese subjects., Conclusion: Fluctuating E(2) levels reflective of follicular development occurred more often among Class 1, 2 and 3 obese women than normal-weight women after DMPA-SC injections. Median MPA levels were consistently lowest among Class 3 obese women but remained above the level needed to inhibit ovulation. Further studies should more fully address the pharmacokinetics of DMPA-SC in extremely obese women.

Background: Combined oral contraceptive (COC) formulations with 20 mcg ethinyl estradiol (EE) have a greater incidence of ovarian hormone production and follicular development, which can be managed by shortening the number of hormone-free days per COC cycle. This study evaluates differences in follicular development during a 7-day versus 4-day hormone-free interval in a COC regimen with 20 mcg EE and 1 mg norethindrone acetate., Study Design: Forty-one healthy women were randomized in an open-label fashion to this formulation in either a 24/4 or a 21/7 day regimen for three cycles. Estradiol, progesterone, follicle-stimulating hormone, luteinizing hormone and inhibin B were measured daily from Cycle 2, Day 21 to Cycle 3, Day 3 and on Day 7 of Cycle 3. Follicular diameter and Hoogland score were calculated on Cycle 2, Days 21, 24 and 28 and Cycle 3, Days 3 and 7., Results: Sixty-six percent of subjects in the 21/7 group and 70% of the subjects in the 24/4 group developed a follicle greater than 10 mm diameter. Ovarian steroid hormone levels, Hoogland scores and bleeding patterns were not statistically significant between the groups., Conclusion: In contrast to prior studies, this analysis suggests no difference in follicle development or bleeding patterns among women receiving a 21/7 or 24/4 regimen of a 20-mcg EE/1-mg norethindrone acetate COC.

Initially approved for use in the United States nearly 50 years ago, oral hormonal contraceptives containing both estrogen and progestin have undergone steady improvements in safety and convenience. Concurrent with improvements in safety associated with decreasing doses of both steroids, there has been an increased incidence of unscheduled bleeding and spotting. There exist no standards regarding data collection techniques and methods, and reporting and analysis of bleeding and spotting events during combined hormonal contraceptive (CHC) trials. For the regulatory review of hormonal contraceptives, data regarding the incidence of bleeding and spotting events are not included in either of the traditional categories of efficacy and safety. Standardization of methods for collecting and analyzing data about cycle control in all clinical trials of CHCs is long overdue. Until such standards are developed and implemented, clinicians need to familiarize themselves with the techniques used in each study in order to provide correct information to their patients about the frequency of bleeding and spotting associated with different formulations and delivery systems.

This is the second of a two-article series describing the outcomes of the Hormonal Contraceptives Trial Methodology Consensus Conference held in Philadelphia, PA, on September 23, 2005. The first manuscript, "Hormonal Contraceptive Trials: Variable Data Collection and Bleeding Assessment Methodologies Influence Study Outcome and Physician Perception," provided a description of methodologies applied in the US Food and Drug Administration medical officer's review of clinical trial data as contained in the Summary Basis of Approvals of New Drug Applications, results of the review and general conclusions. This manuscript provides recommendations regarding best practices in trial design, data collection and analysis regarding bleeding data in combined hormone contraception trials.

Objective: We examined the clinical performance of contraceptive vaginal rings (rings) delivering Nestorone (NES) progestin and ethinyl estradiol (EE). Ring removal times were signaled by menstrual events. Bleeding patterns, adverse events, patterns of use and continuation rates were the principal parameters evaluated., Methods: In a two-stage 6-month trial, subjects were randomized to use rings releasing 50 microg/day of NES and either 10 (50/10) or 20 (50/20) microg/day of EE. Subjects were to keep rings continuously in situ until menstrual bleeding or prolonged spotting-signaled removal. Reinsertion was to occur 96 h later. After the randomized stage, an open-label 6-month trial of rings releasing 150 microg/day of NES and 15 microg/day of EE (150/15) began with the same menstrually signaled regimen., Results: Two-hundred forty-six subjects participated in the trial. Six-month pregnancy rates ranged by ring dose from 1.3 to 3.9 per 100. For each ring dose combination, 6-month continuation rates were above 80 per 100. Bleeding and spotting (B+S) days in women with the 50 microg/day NES rings were similar in number to those experienced by cycling women not using contraception. Nevertheless, in the initial 90 days, fewer B+S days were reported by subjects with the 50/20 ring than by subjects with the 50/10 ring (p < .05). Throughout the trial, subjects using the 150/15 ring reported significantly fewer B+S episodes than did subjects with either 50 microg/day NES ring., Conclusion: Combined contraceptive rings used with a bleeding-signaled regimen led to few terminations attributed to bleeding problems and to acceptable continuation rates. The 150/15 ring appeared to induce fewer bleeding problems than did the lower-dose NES combination rings, but no important difference in 6-month continuation rates among the three doses was noted.

Objectives: This trial tested the hypothesis that menstrually signaled use of contraceptive vaginal rings ("rings") releasing low-dose combinations of Nestorone (NES) and ethinyl estradiol (EE) would reliably suppress luteal activity and ovulation, and prevent unintended pregnancy, while controlling the incidence of menstrual bleeding episodes and bleeding days., Methods: Nestorone/ethinyl estradiol rings releasing 50/10, 50/20 and 150/15 mug/day were studied through 6 months. A ring was to be used continuously, until its removal was signaled by menstrual bleeding. Reinsertion was required 96 h after removal. Serum for NES, EE and progesterone were collected and assayed, and vaginal ultrasound scans were performed in three 5-week periods to examine luteal activity, follicular growth, ovulation and their correlates. In 10 subjects using the 150/15 ring, six samples were drawn in the 24-h period after ring removal to examine serum levels of NES and EE., Results: One hundred sixty subjects at three doses provided blood samples. Median serum concentrations of NES and EE demonstrated dose ratios slightly below the nominal dose ratios expected. Serum NES concentrations declined 19-22% from weeks 3 to 25. Changes in EE levels depended on dose. Nestorone levels fell 81% by 24 h after ring removal and EE levels fell by 50%. Luteal activity was completely suppressed in 94-95% of cycles and in 90% of subjects. Three pregnancies occurred in subjects participating in this serum sampling study., Conclusion: Satisfactory serum levels of NES and EE, and a high level of ovulation suppression were achieved. Irregular ring use, however, permitted pregnancies to occur.

Objectives: The safety and efficacy of a single-rod implantable contraceptive containing etonogestrel (Implanontrade mark) were investigated in a multicenter clinical trial., Study Design: Sexually active American women (N=330) with apparently normal menstrual cycles used the implant for up to 2 years. All subjects recorded bleeding and/or spotting daily in a diary. Safety was assessed through adverse experiences (AEs), laboratory tests and physical and gynecologic examinations., Results: Total exposure was 474 woman-years (6186 cycles), and 68% of subjects had at least 1 year of exposure. No pregnancies occurred. The most common bleeding pattern observed throughout the study was infrequent bleeding, defined as less than three episodes of bleeding in a reference period (excluding amenorrhea). The least common pattern was frequent bleeding, defined as more than five episodes of bleeding in a reference period. Infrequent, prolonged and frequent bleeding patterns were most common early in the study and declined thereafter. During the 3-month Reference Periods 2-8 (Months 4-24), the incidence of amenorrhea ranged from 14% to 20%. Forty-three subjects (13%) withdrew from the study because of bleeding pattern changes and 76 subjects (23%) discontinued because of other AEs. Other common AEs leading to discontinuation, besides bleeding irregularities, were emotional lability (6.1%), weight increase (3.3%), depression (2.4%) and acne (1.5%). Use of Implanon (etonogestrel subdermal implant, referred to herein as ENG implant) for up to 2 years had no clinically significant effects on laboratory parameters, physical and pelvic examinations, vital signs or body mass index. The average length of time required for ENG implant insertion and that for removal were 0.5 and 3.5 min, respectively, and all the procedures were uncomplicated. The return to normal menstrual cycles and fertility was rapid after removal., Conclusions: Implanon is a safe, highly effective and rapidly reversible new method of contraception.

In a multicenter 1-year trial of contraceptive vaginal rings (rings) involving 150 women, three dose combinations of the progestin Nestorone (NES) and ethinylestradiol (EE) were compared with respect to effectiveness, safety and acceptability. Mean in vitro drug release rates for the three doses were 150 and 15, 150 and 20 and 200 and 15 microg/day of NES and EE, respectively. Each ring remained in situ for 21 days, removed for 7 days and then reinserted for a total of 13 cycles of use. We studied ring performance with respect to pregnancy and other termination events, adverse events, the extent of ovulation inhibition, serum drug levels and bleeding control. We also assessed the rings' effects on the vagina using a standardized colposcopy procedure. Seventy-two percent of the women completed the 1-year (> or = 350 days) study. In studied cycles, luteal activity (progesterone > or = 10 nmol/L) was noted in 17%, 7% and 12% of subjects with monitored cycles at the 150/15, 150/20 and 200/15 doses, respectively (p = .34). Two pregnancies occurred, both in subjects using the 200/15 microg/day ring. Breakthrough bleeding during ring use averaged about 2 days/year and breakthrough bleeding and spotting averaged about 7 days/year. In the entire trial, only two women discontinued because of bleeding problems. Medical conditions, chiefly vaginal problems, personal reasons and device loss or repeated expulsion were the principal reasons given for study discontinuation. Vaginal and cervical colposcopy, conducted with standardized techniques and standardized interpretations, revealed no elevated event incidence attributable to ring use. Clinical performance and adverse event profiles indicate that each of these 1-year NES/EE rings, used on a 21-day-in and 7-day-out regimen, provided women effective, acceptable and safe long-acting contraception under their own control.

Depo-Provera is a highly effective contraceptive, given intramuscularly (150 mg/mL) once every 3 months. It has been in use in the United States for over 10 years. A new lower-dose formulation of Depo-Provera (104 mg/0.65 mL), has been developed that allows subcutaneous injection, potentially increasing the convenience, ease of administration and tolerability of this contraceptive. This prospective, randomized, single-center, single-dose trial evaluates the pharmacokinetics of the lower-dose formulation of Depo-Provera and compares the lower-dose formulation to the original formulation with regard to efficacy and duration of ovulation suppression and the return to ovulation at 12 months. While delivering a 30% lower total dose than the intramuscular formulation, the lower-dose formulation of Depo-Provera suppressed ovulation for more than 13 weeks in all subjects and was not affected by body mass index or race. Median time for return to ovulation was 30 weeks, with a 97.4% cumulative rate of return to ovulation at 12 months.

In June 2001, together with an esteemed group of colleagues, I had the opportunity to preside over a 2-day conference presented by the National Institute of Child Health and Human Development that focused on "Preventing Unintended Pregnancy: Advances in Hormonal Contraception." This conference was a well-timed update of a similar program that took place in 1993. In the 8 years since that conference, there have been a number of major advances in the area of contraception. These advances include the introduction of new formulations of oral contraceptives, continued development of existing injectable and implantable delivery methods, and the development and approval of 2 novel delivery systems of contraceptive steroids. The 2001 conference provided a format for the presentation and discussion of these advances, and other important issues that impact both clinicians and patients. Both groups wish to have additional, effective, and safe methods of contraception that are easy to use.

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.

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.

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.

Objective: The purpose of this study was to compare the abortifacient effect of intravaginally administered moistened misoprostol tablets with that of the combination regimen of mifepristone and oral misoprostol., Study Design: One hundred women at

Objectives: This study was undertaken to determine the relief of climacteric symptoms by vaginal rings delivering estradiol and to monitor estrogen levels., Study Design: Rings releasing in vitro either 60 or 140 microg/d estradiol were used by 35 women who had undergone hysterectomy for each dose level. Hot flash and night sweat incidences, vaginal conditions, and complaints were recorded at clinic visits pretreatment and at 1 week, 2 weeks, 1 month, and monthly thereafter through 6 months. Serum samples were assayed for estradiol, estrone, and estrone sulfate., Results: Hot flash incidence was reduced by about 80% with either ring. Vaginal conditions and mood were improved. Fourteen of 70 women discontinued ring use during the trial, 5 because of ring expulsions. Mean (+/-SD) estradiol levels were 123 +/- 48 and 307 +/- 93 pmol/L for the low and high dosage levels, respectively. Mean estrone levels exceeded estradiol levels by 1.7-fold for the higher dosage ring and 2.6-fold for the lower dosage ring. Increases in estrone sulfate concentrations were many times greater than those of estradiol or estrone., Conclusions: Vaginal rings are an acceptable method of delivery for periods of >/=6 months of doses of estradiol that reduce vasomotor symptoms and improve vaginal conditions. There was little difference in these responses between the 2 dosage levels.

A study was undertaken to determine whether the combination of oral tamoxifen and moistened misoprostol administered vaginally was superior to that of placebo and moistened misoprostol administered vaginally for elective termination of early pregnancies.A clinical trial was conducted with a study group of 150 healthy women with pregnancies of

A combined contraceptive vaginal ring designed to last 12 months was tested at three clinic sites. This ring released approximately 1 mg of norethindrone acetate (NET-Ac) and 20 micrograms of ethinyl estradiol (EE) daily. A total of 60 women were enrolled to use the ring in a schedule of 3 weeks in/1 week out. Serum norethindrone (NET) and ethinyl estradiol (EE) levels were assayed twice weekly in cycles 6, 9, and 13. Mean NET concentrations between cycles 6 and 9 were relatively stable between 13 and 19 nmol/L but showed a 10%-21% decrease in all centers between cycles 9 and 13. Mean EE concentrations ranged from 75 to 103 pmol/L, but did not have the same decrease as NET between cycles 9 and 13. Cycles with progesterone peaks (> 9.6 nmol/L) compatible with some luteal activity occurred in 4% of cycles sampled in Sydney, 3% in Santo Domingo, and 26% in Los Angeles. Half of these cycles exhibited at least one progesterone value > 32 nmol/L with three of 18 occurring in noncompliant cycles. Heavier body weight was associated with increased probability of luteal activity. Based on serum estradiol peaks > 400 pmol/L, eight of 81 cycles appeared to have marked follicular activity with no luteal activity. No pregnancies occurred. Nausea was reported by about half the subjects in approximately 10% of the visits (mainly in the first 1-2 days in the first cycle immediately after ring insertion). Vomiting was reported by 20% of subjects early in the first cycle only. Headache was reported on occasion by nearly 50% of the women, but the relationship to ring use was uncertain. Vaginal discharge was reported by 17 women (82% of these were from one clinic). Of 60 women, 14 discontinued before completing the study, but only two discontinuations were for medical reasons. Small but statistically significant changes occurred in lipid levels in two of the three centers. All changes remained within normal limits and were similar to those seen with many oral contraceptives. It appears that this ring may perform slightly differently in different populations, but is a highly satisfactory method of contraception for many women. Minor modifications in design could provide higher levels of steroid release and in the later months of the ring life span would assure continuing high levels of contraceptive protection for heavier women.

Two combined contraceptive vaginal rings (CVR) each releasing approximately 1 mg norethindrone acetate (NET-Ac) and either 20 micrograms or 15 micrograms ethinyl estradiol over 24 h were tested at three clinic sites in Los Angeles, San Francisco, and Sydney. A total of 61 women were enrolled to use the ring on a schedule of 3 weeks in/1 week out for four treatment cycles. Serum estradiol, progesterone, norethindrone (NET), and ethinyl estradiol (EE) levels were assayed twice weekly in all four treatment cycles. Both CVR performed well, with no pregnancies occurring and only one cycle of luteal activity suggestive of ovulation (serum progesterone > 32 nmol/L) occurring with each ring (0.9% of cycles with the 1/15 ring and 1.2% of cycles with the 1/20 ring). Although there was significantly more luteal activity in women using the 1/15 CVR (5.9% compared with 1.2% of cycles), only three cycles with a marked degree of luteal activity (progesterone > 10 nmol/L) occurred among compliant women. Serum levels of NET and EE were consistently elevated during use of both rings. There was no significant difference between serum levels with the two rings because of wide interindividual variations, although both NET and EE levels tended to be higher with the 1/20 ring. However, there was a significant difference in EE levels between the women in Los Angeles and Sydney using the same dose rings. Total cholesterol, HDL, and LDL cholesterol values were not significantly changed during treatment. Triglycerides increased but remained within the normal range. Overall cycle control was good with both formulations, but there was slightly more cycle disturbance with the lower dose ring. There was no change in mean body weight during the study, and individual weight changes appeared to be idiosyncratic. Side effects were infrequent and similar to those reported with other steroidal contraceptive methods. Three women complained of vaginal discharge, one with accompanying itch and one with a vaginal Candida infection in cycle 1. Overall, both of these EE/NET-Ac rings performed well, with only minor and mainly nonsignificant differences in effect on serum EE, NET, E2, and progesterone levels and lipids, and on vaginal bleeding patterns.

The interaction between smoking and oral contraceptive (OC) use with respect to thrombogenesis was investigated by studying the effects of OC and smoking on urinary prostacyclin (PGI2) and thromboxane A2 (TxA2) metabolite levels in smokers and nonsmokers. Sixty healthy women, aged 19-32 years, who were not taking any hormonal treatment for at least 3 months before initiating the study, were divided into three equal groups: OC users who smoked (N = 20), OC users who did not smoke (N = 20), and a control group of 10 smokers and 10 nonsmokers. Each OC treatment group was randomized to receive either norethindrone (NET) acetate (1 mg)/ethinyl estradiol (EE2) (35 micrograms) (N = 10) or NET acetate (1 mg)/EE2 (20 micrograms) (N = 10) daily for 3 months. Overnight urine collections and fasting blood samples were obtained at baseline and at the end of the 3-month study. Serum levels of NET and EE2, as well as urinary levels of cotinine and the stable metabolites of PGI2 and TxA2, namely 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and thromboxane (TxB2), respectively, were measured by specific immunoassays. Analysis of pre- to posttreatment changes in mean urinary 6-keto-PGF1 alpha and TxB2 levels for each subgroup, as determined by smoking status and EE2 dose, showed no statistically significant differences. Also, no significant differences were found in each subgroup with respect to changes in the 6-keto-PGF1 alpha/TxB2 ratios. Large intersubject variability in urinary 6-keto-PGF1 alpha and TxB2 levels were observed in all subgroups. The results of this study indicate that both low-estrogen-dose compounds, when used by smokers or nonsmokers, did not significantly alter the ratio of PGI2 to TXA2 metabolites, compared with pretreatment. However, the small number of subjects and the large intersubject variability in this study make it difficult to determine if there is a significant difference between the 20- and 30-microgram EE2 doses.

The high estrogen doses in the original oral contraceptive (OC) formulations were associated with an increased risk of cardiovascular events. Since then the steroid doses in OC have been reduced steadily, so that current low-estrogen-dose (< or = 35 micrograms) combination OC are associated with a lower risk of arterial and venous events than occurs with higher-estrogen-dose formulations. Based on the currently available epidemiologic evidence, the following conclusions can be made regarding the cardiovascular disease risks associated with use of low-dose OC by healthy, nonsmoking women: there is no increased risk of myocardial infarction (MI) or hemorrhagic or ischemic stroke; and there is a three- to fourfold increased risk of venous thrombosis and embolism (VTE). This risk is about half that associated with pregnancy. Smoking is the most important independent risk factor for MI, and is synergistic with OC use. Women smokers should be advised strongly to stop smoking, but those aged < 35 years may use any OC containing < or = 35 micrograms of estrogen. Women smokers aged > or = 35 years should be advised to use a nonestrogen or nonhormonal contraceptive method.

A 5-year trial of a two-rod contraceptive implant, which releases the progestin levonorgestrel (LNG rod), was conducted at four clinics with 594 women. Mean age and weight at admission were 25.5 years and 62.4 kg, respectively. Consent to continue through 5 years was sought and obtained when the 3-year cumulative pregnancy rate proved to be 0.8 per 100. No pregnancies occurred in the fourth or fifth years. The 5-year cumulative pregnancy rate was, therefore, 0.8 per 100 with an annual average pregnancy rate below 2 per 1000 women. Prolonged bleeding/spotting (8.2% of subjects) and irregular bleeding (5.6%) were the most frequently cited medical reasons for removal. Removals for headache (4.7%) and weight change (4.0%) were the next most frequent medical reasons. Between 1% and 2% of subjects during the 5-year trial sought removals for each of the following conditions: mood changes, lower abdominal pain, depression, or pain at the implant site. The mean annual continuation rate during the study was 77 per 100. Use per woman averaged 2.96 years. Mean removal time was 5.9 +/- 0.6 min. These data indicate that, for a 5-year period, the two LNG rod implants are equivalent to the six Norplant capsule implants with respect to safety and efficacy parameters, but permit easier and more rapid implant removal.

A study was undertaken to determine whether ingestion of the selective estrogen receptor modulator tamoxifen followed by vaginal administration of the prostaglandin misoprostol would be an effective medical method of elective termination of early pregnancy. A clinical trial was conducted with a study group of 100 healthy women with pregnancies of 56 days gestational age or less who desired elective pregnancy termination. Each subject ingested 20 mg of tamoxifen once daily for 4 days followed 4 days later by intravaginal placement of four 200 micrograms tablets of misoprostol. If abortion did not occur within the next 24 h a second dose of 800 micrograms of misoprostol was given. The main outcome measures were incidence of complete abortion, hemoglobin levels, duration of vaginal bleeding, and incidence of side effects. Complete abortion occurred in 92 (92%, 95% CI 86.7, 97.3%) of 100 subjects. Of these 92 women, four aborted after ingesting tamoxifen without use of misoprostol, 84 within 24 h after receiving a single dose of misoprostol, one 21 days following a single dose of misoprostol, and three after a second dose of misoprostol was administered. There were six (6.0%) complete treatment failures and two (2%) incomplete abortions that required a dilatation and curettage. The mean duration of uterine bleeding was 8.1 days (range 1-34 days) and there was a median decrease in hemoglobin level of 0.50 g/dL (+2.2 to -4.7 g/dL). Vomiting occurred in 28% of subjects and diarrhea in 8%. These initial data suggest that ingestion of tamoxifen followed by intravaginal misoprostol may be an effective, easily administered, and inexpensive method to electively induce complete abortion in pregnancies of 56 days gestational age or less. Additional studies are necessary to determine whether the addition of tamoxifen increases the success rate compared with that obtained with the use of vaginally administered misoprostol by itself.

This review has highlighted the attributes of a very important new method of contraception. The signatories to this document agree that, with the provision of appropriate information and instruction for the user, Norplant is a good contraceptive choice to be made available worldwide in family planning programs that have the resources for appropriate training and counseling. The signatories to this document are acting in their own personal capacity and not as representatives of any particular organization.

There is an urgent need to develop safe, effective, and acceptable vaginal products for the prevention of sexually transmitted infections. Preliminary in vitro results suggest that vaginal formulations of sulfated polysaccharides, including iota-carrageenan, have the potential to block mucosal transmission of human immunodeficiency virus (HIV). Twenty-five women in five sites participated in Phase I trials to evaluate the safety of a formulation containing iota-carrageenan (PC 213). The results of this study indicate that a 5 mL 2% gel formulation of iota-carrageenan is not associated with significant irritation of the female reproductive tract when administered once daily in the absence of sexual intercourse. Given the small number of participants in this initial study, careful observation for potential irritation must also be included in larger studies of this and other vaginal formulations.

Forty-two healthy women volunteered to have blood samples drawn at 2, 4, 8, 24, 48, and 168 h (7 days) following placement of levonorgestrel-releasing rod (LNG rod) or of Norplant capsule implants to permit measurement of drug concentrations. Three clinics recruited 10 women each, half of whom used each type of implant. Twelve additional subjects were later enrolled at one site to provide greater detail for the capsule implants. Throughout the week, women with Norplant implants had apparently higher mean drug concentrations than did women with LNG rod implants, but the differences were significant only in the first 48 h after placement (p < 0.05). Maximum levels for capsule implants were found at the 24-h sample (mean, 1358 to 1474 pg/mL) and for the LNG rod implants at 48 h (772 pg/mL). Body weight was negatively correlated with levonorgestrel concentrations at all times (p < 0.05). For several sampling times, differences between clinics in mean concentrations were statistically significant after weight adjustment. Despite differences by implant type, weight, or clinic location, drug concentrations compatible with contraceptive effect were attained within 24 h in users of LNG rod or of Norplant implants, insofar as all women had levonorgestrel concentrations above 250 pg/mL at the 24-h sample.

The study population included 159 women aged 18 to 37 years requiring contraception (60 in Sydney, 99 in Los Angeles). The design consisted of a 6 month study of a contraceptive vaginal ring (CVR) releasing 20 micrograms ethinyl estradiol and 1 mg of norethindrone acetate daily over two successive cycles with a new ring on each of three different insertion regimens. A total of 831 woman-months of exposure were recorded, and 129 women completed the study. The overall incidence of side effects was similar in the two centers and differences between the insertion regimens were not observed. Transient nausea following insertion of a new ring (mainly lasting 0.5 to 48 h) was the most prominent side effect, with no significant difference between the insertion regimens (although the incidence tended to be highest with bedtime insertion [34%] and lowest with early evening insertion and temporary removal during the first night [27%]). Transient vomiting occurred in about 10% of women in the first 24 h after first insertion of a new ring. The incidence and severity of nausea was greatly reduced in cycle 2 with each regimen (6% to 9% of women). Nausea could be prevented by overnight soaking of the ring in water before use. Other side effects such as headache, dizziness, uterine cramps, breakthrough bleeding, weight gain, and ring expulsion occurred with similarly low frequency in all three insertion groups. One pregnancy occurred with probable ovulation between cycles 5 and 6, the only pregnancy recorded to date in studies with this ring. The study demonstrated that this effective and generally well tolerated CVR causes a relatively high incidence of transient nausea after insertion of a new ring, which is probably due to accumulation of ethinyl estradiol on the ring surface during storage. Acceptability is still high, and this particular CVR merits further development.

From approximately one week before normal ovulation resumes, lactating women require protection against pregnancy by a contraceptive that is safe for both infant and mother in a multicenter one-year study, the natural hormone, progesterone, delivered vaginally by a sequence of four contraceptive rings designed for continuous use, was evaluated as a contraceptive for nursing mothers in comparison with the Copper T 380A IUD. Individual rings release in effective average dose of 10 mg day for a 3 month period. Evaluation included measures of lactational performance as well as of contraceptive efficacy and safety to mother and child. Nine participating clinics enrolled 802 ring users and 734 IUD acceptors between postpartum days 29 and 63. Life table analyses were performed with parallel decrements for ring and IUD subjects. Continuation in the study and analysis required that subjects not stop breastfeeding. The ring, with a one-year pregnancy rate of 1.5 per 100, did not differ significantly from the IUD with respect to contraceptive effectiveness (p > 0.05). More than half of the ring subjects were continuing at 6 months post admission and a quarter (23.5 per hundred) were still using the ring and breastfeeding one year after admission. Women with the IUD, however, had higher continuation rates (p < 0.001) at both time points. The largest single decrement for each method was that for weaning. Ring users had more complaints of vaginal problems but had fewer vaginal disorders on examination. At 12 months postpartum, 46 per 100 continuing ring users remained in amenorrhea. Lactation performance and the health and weight gain of the infants were similar among users of either regimen.

In a three-year randomized trial that included 398 women, blood samples were collected for the purpose of assaying levonorgestrel concentrations in women using a new two-rod contraceptive implant system or an earlier implant formulation, Norplant-2 implants. Sample collection was at 1, 3, 6, 9, and 12 months after placement and semiannually thereafter through three years. Resulting assays and analyses showed that levonorgestrel concentrations of each implant formulation decreased significantly with time after placement, with increasing body weight, and with ponderal index. In the third year, several measures indicated that concentrations of the contraceptive drug were higher in women using the LNG ROD implants than in users of the original formulation. No pregnancies occurred among women in either group in the three years. This study provides evidence that the minimum levonorgestrel concentration needed to protect against pregnancy is below 200 pg/ml, and possibly is below 175 pg/ml.

Objective: Our purpose was to determine whether intracervical placement of laminaria tents would improve the effectiveness of the prostaglandin analog misoprostol for the elective termination of pregnancies in the second trimester., Study Design: Sixty-eight women between 12 and 22 weeks of gestation with either an intrauterine fetal death (n = 40) or medical or genetic indications for pregnancy termination (n = 30) were randomized to receive 200 micrograms of misoprostol administered vaginally every 12 hours with or without intracervical placement of laminaria concurrently with the first dose of misoprostol., Results: The rate of abortion 24 hours after initiation of treatment was 69.7% in the 33 women receiving misoprostol alone and 68.6% in the 35 women treated with misoprostol and laminaria. The abortion rates 48 hours after initiation of treatment were 84.8% and 91.4%, respectively, an insignificant difference. The complete abortion rate was also similar between women receiving misoprostol alone (39.3%) and the group receiving misoprostol and laminaria (37.5%). There were no significant differences in the incidence of fever, vomiting, diarrhea, or pain. The mean interval from initiation of treatment to abortion was also similar, 15.7 hours in those receiving misoprostol alone and 17.4 hours in those treated with misoprostol and laminaria. In both groups women who had live fetuses at the start of the procedure had a higher failure rate of abortion and a longer time interval to abortion than women whose fetus was dead., Conclusions: Laminaria tents inserted concurrently with the first dose of misoprostol do not significantly improve the abortifacient effect of vaginal misoprostol in the second trimester of pregnancy.

To compare the clinical performance of the TCu380A, the most widely used copper IUD in the world today, and a new frameless device, the Cu-Fix, we report results from a randomized international two-year clinical trial involving 874 parous women followed for an average of fourteen months. Event rates at the end of two years (per 100 women) for pregnancy were 0.0 for the TCu380A and 1.5 for the Cu-Fix. Termination due to expulsion was significantly less for TCu380A as compared with Cu-Fix users (2.0 and 11.4 per hundred women, respectively); other medical reasons for termination (bleeding/pain, pelvic inflammatory disease (PID), and other) did not differ significantly. PID incidence rates at two years were 1.0 per hundred women for the TCu380A and 1.6 for the Cu-Fix (equivalent to 6.0 and 8.3 per 1,000 woman-years, respectively). The net cumulative continuation rates at two years per hundred women were 78.8 for TCu380A, and 71.9 for the Cu-Fix. Both IUDs provide highly effective protection against pregnancy, but the TCu380A has a lower expulsion rate. The low rate of PID indicates that it is an in-frequent occurrence in appropriately selected candidates.

Misoprostol is a prostaglandin analogue which has uterotonic properties. Administered vaginally, it is an effective agent for induction of second trimester abortions. This study was undertaken to determine if the vaginal administration of misoprostol is effective for inducing first trimester abortions. Fifty-eight women with pregnancies less than 10 weeks gestation who desired pregnancy termination received varying dosages of vaginal misoprostol, either alone or in combination with laminaria or tamoxifen. The overall success rate for a complete abortion was 61%. The use of laminaria or tamoxifen did not affect success rates. Abortions occurred within 24 hours of administration of misoprostol. Side effects were minimal. There were no significant differences in any of the following between those who had a successful abortion and those who did not: gravidity, parity, prior elective abortion, age, gestational age of the pregnancy, and level of human chorionic gonadotropin. Although not as successful as other combination regimens, misoprostol alone is readily available, easy to administer, and without major side effects. The use of this agent could eliminate the need for about two-thirds of surgical abortions in the first 10 weeks of gestation.