Contraception: Contraception with NORPLANT(R) implants

NORPLANT^® progestogen-only implant contraception providesseveral years of effective protection against pregnancy followinga single application. It is reversible whenever desired, withreturn to normal fertility. Drug release and concentrationsare maximal in the first month of use, when a set of six capsulesreleases 85/µg/day of levonorgestrel. Release is 25–30/µg/dayat 60 months. Circulating drug concentrations and pregnancyrates vary inversely with body weight at placement, but evenamong heavier women, failure rates are below those of oral contraceptivesin the general population. Side-effects are most marked at theinitiation of use. Disruption of normal menstrual patterns occursin 70–80% of recipients initially. Menstrual blood lossis decreased, however, and most women experience modest increasesin haemoglobin. Headache, acne, other skin or hair problems,changes of weight and of mood and abdominal pain, are the mostcommon side-effects attributed to NORPLANT^® contraception.The frequency of occurrence of side-effects diminishes withincreased duration of use. The comparative paucity of majorside-effects, coupled with the method‘s convenience andeffectiveness and its very long action have made NORPLANT^®implants highly acceptable in both developing and developedcountries.     

A clinical trial of 7 alpha-methyl-19-nortestosterone implants for possible use as a long-acting contraceptive for men

Several preparations of testosterone and its esters are being investigated alone or in combination with other gonadotropin-suppressing agents as possible antifertility agents for men. We studied the effectiveness of 7 alpha-methyl-19-nortestosterone (MENT) as an antispermatogenic agent in men. MENT has been shown to be more potent than testosterone and to be resistant to 5 alpha-reduction. For sustained delivery of MENT, we used a system consisting of ethylene vinyl acetate implants containing MENT acetate (Ac), administered subdermally. Thirty-five normal volunteers were recruited in 3 clinics and were randomly assigned to 1 of 3 doses: 1 (12 men), 2 (11 men), or 4 (12 men) MENT Ac implants. The initial average in vitro release rate of MENT Ac from each implant was approximately 400 micro g/day. Implants were inserted subdermally in the medial aspect of the upper arm under local anesthesia. The duration of treatment was initially designed to be 6 months. However, in 2 clinics the duration of treatment was extended to 9 months for the 2-implant group and to 12 months for the 4-implant group. Dose-related increases in serum MENT levels and decreases in testosterone, LH, and FSH levels were observed. Effects on sperm counts were also dose related. None of the subjects in the 1-implant group exhibited oligozoospermia (sperm count, <3 million/ml). Four subjects in the 2-implant group became oligozoospermic, 2 of whom reached azoospermia. Eight subjects in the 4-implant group reached azoospermia, with 1 exhibiting oligozoospermia, whereas 2 were nonresponders. Side effects generally seen with androgen administration, such as increases in erythrocyte count, hematocrit, and hemoglobin and a decrease in SHBG, were also seen in this study and were reversible. Changes in lipid parameters were moderate and transient. Liver enzymes showed small changes. This study demonstrates that MENT Ac, when administered in a sustained release fashion via subdermal implants, can inhibit spermatogenesis over a prolonged period after a single administration and has the potential to be used as a male contraceptive.     

Two-year prospective study in Colombia of Norplant implants

A clinical trial of levonorgestrel-releasing Norplant implants used for contraception was undertaken in two cities in Colombia. Through two years in which 389 women had accumulated 594 years of use, there were no pregnancies. In a comparison group of copper intrauterine device acceptors, the one-year pregnancy rate was 1.1 per 100. Menstrual disturbances associated with progestin-only administration were the principal side-effects, and the major reason for cessation of use. Continuation among users of the implants was at the same or at a higher rate than observed among users of the intrauterine device. Advantages and disadvantages of alternate sites for implant placement are discussed.     

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.     

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.     

Effectiveness of medical abortion with mifepristone and buccal misoprostol through 59 gestational days

Background

From 2001 to March 2006, Planned Parenthood Federation of America (Planned Parenthood) health centers throughout the United States provided medical abortions principally by a regimen of oral mifepristone, followed 24-48 h later by vaginal misoprostol. In late March 2006, analyses of serious uterine infections following medical abortions led Planned Parenthood to change the route of misoprostol administration and to employ additional measures to minimize subsequent serious uterine infections. In August 2006, we conducted an extensive audit of medical abortions with the new buccal misoprostol regimen so that patients could be given accurate information about the success rate of the new regimen.

Objectives

We sought to evaluate the effectiveness of the buccal medical abortion regimen and to examine correlates of its success during routine service delivery.

Methods

In 2006, audits were conducted in 10 large urban service points to estimate the success rates of the buccal regimen. Success was defined as medical abortion without vacuum aspiration. These audits also permitted estimates of success rates with oral misoprostol following mifepristone in a subset in which 98% of the subjects stemmed from two sites.

Results

The effectiveness of the buccal misoprostol-mifepristone regimen was 98.3% for women with gestational ages below 60 days. The oral misoprostol-mifepristone regimen, used by 278 women with a gestational age below 50 days, had a success rate of 96.8%.

Conclusion

In conjunction with 200 mg of mifepristone, use of 800 mcg of buccal misoprostol up to 59 days of gestation is as effective as the use of 800 mcg of vaginal misoprostol up to 63 days of gestation.     

Comparison of the impact of vaginal and oral administration of combined hormonal contraceptives on hepatic proteins sensitive to estrogen

OBJECTIVE: We evaluated the effects of a new combined hormonal contraceptive vaginal ring (CVR) delivering the nonandrogenic progestin Nestorone (NES) and ethinyl estradiol (EE) on several key estrogen-sensitive hepatic proteins that may be markers for the risk of arterial or venous disease events and on blood pressure (BP). Because the pharmacologic androgenicity of the progestin in these formulations influences the hepatic impact of EE, we selected an oral contraceptive (OC) delivering the androgenic progestin levonorgestrel (LNG) and EE as the comparator. We also investigated the effect of delivery route, which is known to modify the hepatic effects of estradiol, but has not been widely studied with EE. STUDY METHODS: Women, aged 18-34 years, with no contraindications to the use of combined OCs, were randomized to three cycles of treatment with a CVR delivering NES/EE (150/15 microg/day) or a combined OC providing LNG and EE (150/30 microg per tablet). Each cycle consisted of 21 days of active treatment, followed by 7 days without treatment. During the last weeks of the pretreatment and third treatment cycles, blood samples were obtained for determinations of plasma concentrations of angiotensinogen, an estrogen-sensitive hepatic protein, and serum concentrations of sex hormone-binding globulin (SHBG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG) and estrogen- and androgen-sensitive proteins. BP was also measured. RESULTS: Of 47 women randomized, 45 completed the study (CVR: 23; OC: 22). Within-group comparisons over time by repeated-measure analysis of variance demonstrated statistically significant changes over time with both treatments for all hepatic proteins (p < .02) but not for TC. The within-group effects, presented as relative percent difference [95% confidence interval (CI)], were greatest for angiotensinogen [CVR: 227% (195-262%); OC: 251.3% (218-288%)] and SHBG [CVR: 306% (237-389%); OC: 55% (30-86)]. Both treatments were associated with small changes in systolic BP and diastolic BP (DBP), but only the within-group change in DBP for the OC group was statistically significant (p = .04). Between-treatment comparisons of third treatment cycle mean values were performed by analysis of covariance (baseline values as covariate). No statistically significant between-treatment differences were found for angiotensinogen, sensitive only to estrogen, or BP. Statistically significant treatment differences were found for all estrogen- and androgen-sensitive proteins (p < or = .002) but not for TC. When presented as relative percent difference between the effects of treatment (CVR-OC/OC; 95% CI of percent difference), the difference was largest for SHBG (159% [117-210%]); smaller relative percent differences were found for HDL-C [31.9% (18.5-46.8%)], LDL-C [23.6% (33.4% to -2.4%)] and TG [39.0% (14.0-69.4%)], but not TC. CONCLUSION: Vaginal delivery of a combined hormonal contraceptive did not reduce the EE-associated changes in estrogen-sensitive hepatic proteins observed after use of a combined OC. Significant treatment differences between the NES/EE CVR and the LNG/EE OC were found for SHBG, HDL-C, LDL-C, and TG, proteins sensitive to androgen as well as estrogen. No treatment difference was observed for angiotensinogen, which is sensitive only to estrogen. The observed treatment differences were therefore most likely due to the difference in androgenicity between NES and LNG.     

A randomized trial of the Gyne T 380 and Gyne T 380 Slimline Intrauterine Copper devices

To facilitate manufacture and insertion of the Gyne T 380 IUD, design changes were instituted. Copper collars were seated flush at the ends of the horizontal crossbar of the device. A randomized study of the Gyne T 380 Slimline, the new design, was undertaken in comparison with the standard Gyne T 380. A total of 996 women were enrolled, with 698 Slimline insertions and 298 of the standard Gyne T. No statistically significant difference in ease of insertion or in performance was detected between the models. At one year, the pregnancy rate of each model was below 0.5 per 100 and the continuation rate was 79-80 per 100. Pelvic inflammatory disease or endometritis was found in one percent of subjects in the first year. This is the seventh multicenter randomized study of a collared T IUD with 380 mm2 of copper surface. In all seven, the one-year gross pregnancy rate has been 1.2 per 100 or lower.     

International experience with NORPLANT and NORPLANT-2 contraceptives

Experience encompassing more than 20,000 woman-years of use of NORPLANT capsules and 6,000 woman-years of trials of NORPLANT-2 rods is reviewed. Implant contraception repeatedly has been associated with low pregnancy rates and high continuation rates through five full years of use. Weight has proved to be a factor related to effectiveness. Women weighing less than 50 kg experienced cumulative five-year pregnancy rates well below 1 per 100, whereas the overall cumulative rate has been 3.5 per 100. Medical events reported during use that have led to discontinuation are analyzed from four large data sets.