Levonorgestrel 38 mg subdermal implant (Norplant), intended to provide contraception for 5 years, was withdrawn in the UK in 1999 due to unwanted effects (menstrual disturbances) and difficulties in removing the device. Since then, [symbol: see text]etonogestrel implant (Implanon-Organon), another progestogen--only subdermal contraceptive device, has become available in the UK. The manufacturer claims that etonogestrel implant provides contraception for up to 3 years and is easy to insert and remove. Here, we consider the place of etonogestrel implant.

NORPLANT was introduced into the Chinese family planning programmes in 1984 by the Population Council. After a pilot study of 1200 cases in four centres in China, the study was expanded to 12 centres with 10,718 cases of NORPLANT and 1208 cases of NORPLANT-2 followed up for more than 6 years. The 5 years net cumulative pregnancy rates were 0.5-1.2 and the net cumulative continuation rates were around 65-72 per 100 users. There were significant differences in pregnancy rates between different groups of body weight and age, i.e. the pregnancy rates were higher in groups with body weight over 70 kg and those aged below 25 years. The age, body weight and dependence on contraceptive effectiveness of NORPLANT should be taken into account in the selection of users. Nationwide large-scale studies in provincial and country rural areas and postmarketing surveillance are being carried out. Changes in ovarian function and endometrium have been studied. Levonorgestrel IUD (LNg-IUD) was introduced into China in 1985. Comparative clinical studies on NORPLANT and LNg-IUD, pharmacokinetic and pharmacodynamic studies and endometrial studies of LNg-IUD were performed. The higher percentage (55.1%) of ovarian suppression in Chinese users of LNg-IUD may be attributed to ethnic differences among Caucasian women in their susceptibility to steroid hormones. Results showed favourable acceptance of both devices among Chinese women. The studies promoted the incorporation of new long-acting contraceptive methods into the Chinese family planning programmes.

Long-acting forms of contraception that take advantage of the tissue compatibility of silicone rubber, a polymer of dimethylsiloxane, have been developed. The most advanced type of subdermal contraceptive capsule contains about 36 to 40 mg of levonorgestrel and is 30 mm in length and 2.4 mm in diameter (Norplant). The set of six implants is placed under the skin of the upper arm with a 10-gauge trocar with the use of a local anesthetic. The basis for the antifertility effect of these implants is continuous, low-dose progestogen therapy without the use of estrogen. The capsules release a total of approximately 39 micrograms of levonorgestrel each day. The blood progestogen level achieved through this microabsorption delivery system is 0.25 to 0.3 ng/ml. There is a sufficient supply of steroid in the capsules to maintain this blood progestogen level for 5 to 6 years. Since the capsules can be removed at any time, this contraceptive method is voluntarily reversible. The effectiveness of these subdermal implants has been evaluated in long-term studies that have progressed for well over 5 years. Therefore one clinic visit eliminates nearly 2000 days of concern over having to remember to take a pill on schedule. There has been sufficient experience to assure that fertility recurs promptly after removal of the subdermal implants.

OBJECTIVE

To study the endocrinologic profile of regularly menstruating users of levonorgestrel subdermal implants.

METHODS

Observational, prospective, case-controlled comparative study.

METHODS

The Family Planning Clinic of PROFAMILIA, in Santo Domingo, Dominican Republic.

METHODS

Thirty one regularly cycling Norplant users and 12 nonhormonal contraceptors who volunteered to participate.

METHODS

Norplant contraceptive implants were inserted in 31 subjects between 13 and 77 months before this study.

METHODS

Follicle-stimulating hormone, luteinizing hormone, estradiol (E2), and progesterone (P) were serially assayed for one menstrual cycle.

RESULTS

Almost half of the cycles among Norplant users were anovulatory; all the rest (55%) had some form of dysfunction: diminished gonadotropin surge, luteal phase insufficiency (low P levels and shortened luteal phase), and E2 profiles different from normal controls.

CONCLUSIONS

Anovulation is clearly one of the main mechanisms of action of Norplant, but even in presumptive ovulatory cycles, the dysfunctions described possibly contribute to the high contraceptive effectiveness of Norplant.

OBJECTIVE

To examine maternal influence and related variables on adolescents' decision to adopt Norplant.

METHODS

A prospective study of 121 adolescent females who received Norplant through a hospital-based outpatient adolescent gynecology service. Each patient completed self-report questionnaires about her decision process, sexual behaviors and standardized measures of depression and anxiety at their insertion appointment or first-follow-up appointment.

RESULTS

Almost 40% of the sample reported that their mother significantly influenced their decision to use Norplant and 61% of all patients stated that they had informed their mother of their choice of this contraceptive method. Through logistic regression, six variables were found to be significantly associated with mother as the most important decision source. These included: obtaining information about Norplant from a parent, maintaining the same sexual partner, past pill use, and not knowing other adolescents who boast about using the Norplant system.

CONCLUSIONS

These data suggest that when parental consent is not required, adolescent females disclose sensitive information regarding choice-making to their mothers when they decided to adopt Norplant.

OBJECTIVE

To determine the safety and efficacy of Norplant (Wyeth-Ayerst Laboratories, Philadelphia, PA) insertion immediately postpartum.

METHODS

Prospective study of 14 women receiving Norplant immediately postpartum compared with controls (n = 6) having a bilateral tubal ligation. Subjects were followed for 3 months postpartum, and data were analyzed by analysis of variance and chi2.

METHODS

Academic Health Sciences Center.

METHODS

Female subjects 18 to 35 years old who had an uncomplicated term pregnancy, normal spontaneous vaginal delivery, and did not breast-feed.

METHODS

A brief interview, physical exam, and blood and urine samples were evaluated during a 12-week postpartum period.

METHODS

Major complaints, serum chemistry panels, hematologic and coagulative measures, serum E2, P, levonorgestrel, PRL, LH, FSH, and urinary estrone-3 conjugates and pregnanediol-3-glucuronide concentrations.

RESULTS

Serum levonorgestrel peaked at approximately 2,000 pg/mL (6,400 pmol/L) during the 1st week after Norplant insertion, declining to approximately 250 pg/mL (800 pmol/L) by the 8th week. Significant differences between Norplant and control groups included bleeding irregularities, headaches, alopecia, and abdominal discomfort. Serum electrolytes, metabolic markers, and blood components were within normal limits. Serum E2, P, and urinary steriod biomarkers indicated that steroid secretion was suppressed severely in the Norplant group compared with controls who exhibited normal postpartum ovarian activity.

CONCLUSIONS

Norplant inserted immediately postpartum appears to be a safe and effective method of contraception. However, the long-term hypoestrogenic state and contraceptive efficacy beyond the 3-month postpartum period as observed in this study are concerns that need further clinical evaluation.

The Norplant* system is composed of a set of six Silastic* (silicone polydimethysiloxane) capsules measuring 34 mm by 2.4 mm, each containing 36 mg of levonorgestrel and sealed at either end with a medical grade silicone elastomer adhesive. Levonorgestrel is a synthetic progestin, widely used in combination oral contraceptives and in single-agent "mini-pills". In a procedure completed in less than 15 minutes by an experienced physician, the six capsules are surgically implanted subdermally, most commonly on the inside of the left upper arm. The levonorgestrel diffuses through the Silastic material into the blood stream and is carried to the target organs. Ovulation is suppressed in the majority of the cycles during the first years of use, and cervical mucus is thickened, inhibiting sperm penetration. During use, the effective delivery of levonorgestrel is about 30 mcg/day from day 500 to day 2300. Recently, we have seen patients with complications from Norplant, and we describe here a patient who presented with systemic complications resulting from both the endocrinological aspects of Norplant and the immunological aspects of the Silastic implants. To our knowledge this is the first case report in the western medical literature describing systemic immunological complications as a result of a failed Norplant device.

OBJECTIVE

To study the probability of ovulation and subclinical abortion during long-term use of Norplant and to assess the concomitant endometrial development.

METHODS

This was a prospective nonrandomized comparative study. The ovaries and endometrium were assessed daily by ultrasonography during 59 menstrual cycles in 50 women who were using Norplant for>> 1 year. Serum concentrations of E2, P, FSH, LH, pregnancy specific beta 1 glycoprotein (Sp1), and hCG were also daily measured. The findings were compared with those in 35 ovulatory cycles in normal fertile women not using contraception.

METHODS

Clients of the Family Planning Clinic of Assiut University Hospital (Norplant users) and the hospital women staff (controls).

RESULTS

Sonographic and hormonal evidence of ovulation were observed in one third of Norplant users; two of them resulted in conception. However, the majority of these ovulatory cycles showed low midcycle peaks of E2, FSH, and LH and evidence of luteal phase defect (LPD). Excessive follicular enlargement was observed in 46% of the cycles. Norplant users had significantly thinner endometrium that did not exhibit the normal phasic changes in sonographic texture. Apart from conceptive cycles, no rise in Sp1 or hCG was observed.

CONCLUSIONS

Norplant acts mainly by inhibiting ovulation, but when this occurs, it is associated with LPD and subnormal endometrial development. Subclinical abortion does not contribute to the contraceptive effect.

The aim of this study was to characterize the bleeding pattern, the outcome of pregnancies and the levonorgestrel plasma levels associated with method failures in Norplant implants users. Nineteen pregnancies are reported in 458 woman and 21,589 woman-months observed during the first eight years of Norplant use. Pregnancy rates increased slightly during the first six years of use, attaining a Pearl Index above three thereafter. All women who became pregnant had experienced a regular bleeding pattern in the six months preceding conception. Levonorgestrel plasma levels observed at different intervals before conception and during the conceptional cycle were similar to those observed in non-pregnant women at comparable intervals after Norplant insertion. The nineteen pregnancies ended in thirteen term deliveries, one premature delivery, three abortions and two ectopic pregnancies. No abnormalities were found in the infants. The two ectopic pregnancies are the only ones reported for Norplant users in The Population Council studies. The overall incidence is less than 0.8 per 1000 woman-years.

Two-hundred-and-eighty Indonesian women were provided with Norplant, a levonorgestrel-releasing implant. At various time intervals, up to 5 years after Norplant insertion, levonorgestrel and sex hormone binding globulin (SHBG) were assayed in blood plasma. After an initial burst of approximately 7 nmol/l, the levels of levonorgestrel rapidly decreased during the first month. The decrease continued to a nadir (1.1 nmol/l) which was reached 10 months later. The decrease was followed by an increase to a broad peak of 1.5 nmol/l which was reached 2 years after insertion. Thereafter, a slow-decrease at a rate of approximately 18 pmol/month was seen. SHBG levels decreased significantly already 1 week after insertion. A nadir of levels (25 nmol/l) was reached 3 months later. The levels increased slowly again and remained constant (32 nmol/l) from about 15 months to 5 years. During the entire period of study highly significant correlations of levonorgestrel with SHBG were seen. In another group of 25 women the levels of levonorgestrel and SHBG were studied before and one week after insertion of Norplant. A significant correlation (r = 0.77) was found between the preinsertion levels of SHBG and postinsertion levels of levonorgestrel.

BACKGROUND

The aim of this study was to assess user acceptability and effectiveness of implant contraception in Singaporean women.

METHODS

A prospective study was carried out on 553 patients who received Norplant implant in our hospital from 1 January 1992 to 31 December 2000, and followed-up till 15 July 2003. The patients' profile, side-effects, satisfaction and continuation rate of Norplant implant were studied.

RESULTS

The mean age of the subjects was 29.4 (plus or minus 5.1) years. The mean parity was 2.1 (plus or minus 1) live births. More than one-half (55.2 percent) of the subjects had used other methods of contraception before. The main reason for them to switch to implant contraception was convenience (63.6 percent). Of the 516 users on follow-up, the common side-effects were menstrual irregularity (51 percent), secondary amenorrhoea (9.6 percent) and weight gain (15.7 percent). 29.3 percent of users did not experience any side-effect. There was only one contraceptive failure, which may be related to drug interaction. The Pearl Index was 0.054 per hundred women years. There was only one serious adverse event of a patient (0.2 percent) who developed severe hypertension requiring treatment. The continuation rate was 92.4 percent after one year, 80.8 percent after two years, 68.9 percent after three years and 58.5 percent after four years. The main reasons for early implant removal were side-effects and desire for future pregnancy. Re-insertion was carried out in 53.7 percent of users who had completed five years of Norplant contraception.

CONCLUSIONS

This largest sub-dermal hormonal implant contraception study in multi-racial Singapore showed that Norplant contraception had a high degree of effectiveness with relatively high user satisfaction and continuation rate.

It is possible that women of certain ethnic backgrounds, specifically those more prone to keloid formation, are also more prone to the insertion site complications of levonorgesterel implants. Failure to recognize the potential for this complication and to provide adequate guidance to the patient could result in unwarranted cost and complications. It is possible that intralesional steroid injection at the first sign of a local reaction will minimize the formation of a keloid; however, specific research will need to be done before a change in practice can be recommended.

Methods of reversible contraception, oral contraceptives, intrauterine devices, and Norplant (systemic progestin-only contraceptive; Wyeth-Ayerst, Radnor, PA), can be used for women over 35 years of age. Oral contraceptive formulations are safe and effective for healthy women up to the age of menopause. Oral contraceptives in women who do not smoke cigarettes do not result in a significant increased risk for cardiovascular disease. The incidence of breast cancer is not increased in women who have used oral contraceptives. A slight increase was found in younger women who had been on oral contraceptives based on a reanalysis of the contraceptive and steroid hormone study of the Centers for Disease Control. A reduction in the incidence of ovarian epithelial neoplasia by 40% was found in three European case-control studies. Two intrauterine devices are currently available on the US market: Paragard (GynoPharma, Somerville, NJ) and Progestasert (Alza Corp., Palo Alto, CA). Both of these provide highly effective contraception. A World Health Organization prospective randomized study found that there was an increase in pelvic inflammatory disease rates in the first 20 days after intrauterine device insertion. The intrauterine device itself did not increase the pelvic inflammatory disease incidence rates. The Norplant system exerts its contraceptive action through ovulation inhibition and alteration of cervical mucus. The major consumer complaint is irregular or prolonged uterine bleeding, which can be controlled by oral estrogen.

This work was done in search for a model to examine target organ response to fluctuations in serum levels of sex hormone-binding globulin (SHBG) and its ligands. The time course and magnitude of fluctuations of SHBG, levonorgestrel (L-Ng), estradiol (E2), testosterone (T) and dihydrotestosterone (DHT) in serum were examined during and after treatment with 50 ug of ethinylestradiol (EE2) daily for 10 days in 10 volunteer women using NORPLANT implants. Six of these volunteers were also treated with 20 ug of EE2 daily for 7 days and two additional volunteers using a copper-T IUD were treated with 50 ug of EE2 daily for 7 days. In all cases, SHBG and L-Ng levels increased in a close parallel manner several-fold above basal levels during treatment, reaching a maximum around two days after the last EE2 pill. In contrast, the levels of E2 and T increased in one subject, decreased in 5 and remained unchanged in 4, while changes of DHT were unrelated to those of the other ligands. Since the L-Ng "secretion rate" by NORPLANT implants is constant, it follows that the effect of EE2 on its levels is due to a decreased metabolic clearance rate, most likely secondary to the increased binding of L-Ng to SHBG in serum. This interpretation is in agreement with the close parallelism in the fluctuations of L-Ng and SHBG. It is concluded that in NORPLANT users, SHBG and L-Ng, but not the endogenous ligands, behave in a predictable manner in response to EE2. Thus, this model affords the possibility of exploring the influence of SHBG on tissue response to progestins.

In response to the need of some women for long-acting, effective and safe contraceptives, the scientific community developed non-biodegradable progestational subdermal implants that act by making the cervical mucus viscous, with ovulation inhibition and thinning of the endometrial lining. The contraceptive protection is within 24 hours and the cumulative failure rate is low. Contraceptive implants require little or no motivation following adequate counselling. In current use are multirod implants (Norplant I and Norplant II Jadelle) and single rod implant (Implanon and Uniplant). Although menstrual symptoms associated with progestational regimens are the major compliance and acceptability factors within the first year of use, menstrual disturbance generally improves. Continuation rates for implant use are high among those who have had adequate pre-insertion counselling because the perceived advantages greatly outweigh the nuisance effects. Other side effects of implants are similar to those observed with hormonal pills--headache, weight changes, mood swings and abdominal bloating. Training of physicians and nurses in the art of insertion and removal techniques is a pre-requisite for a successful implant programme. This should also be backed by integration of implants into the national commodity logistics systems to ensure adequate local budgetary provision for contraceptive implant procurement rather than reliance on donor supply.

The effect of Norplant-2 rods on liver, lipid and carbohydrate metabolism was evaluated in 100 women using Norplant-2 rods. Besides a significant increase in serum bilirubin, there was no other obvious evidence to suggest any possible hepatocellular dysfunction with the use of Norplant-2 rods. As regards lipid metabolism, decreases in total triglycerides, cholesterol and LDL-cholesterol and HDL-cholesterol were initially seen. These parameters returned to their preinsertion mean at the end of five years. As a result, the value of the HDL-cholesterol/total cholesterol - HDL-cholesterol and LDL-cholesterol/HDL-cholesterol ratios remained around their preinsertion value at the end of five years. All this appears to indicate that the use of Norplant-2 rods is not directly contributory to cardiovascular risk. The use of Norplant-2 rods was not associated with any significant effect on carbohydrate metabolism.

Daily transvaginal ultrasound (US) scanning of the ovaries to assess follicular development and daily blood sampling were performed on 19 Norplant (Leiras, Turku, Finland) subdermal contraceptive implant users who had regular menstrual cycles and on 10 normally cycling women. Three groups were identified in the implant users based on US finding. Six (31.6%) of the implant users had US findings that were consistent with a normal ovulatory pattern. However, their mean peak luteinizing hormone levels and peak midluteal phase progesterone (P) levels were significantly lower than control values. Eleven (57.9%) users had persistent follicles, and 2 users (10.5%) had no follicular development. These data suggest that after 2 to 4 years of use, about one third of Norplant users with regular bleeding patterns may ovulate but most have deficient luteal P levels. In this small study, the presence of persistent follicular enlargement in implant users was common.

The article describes how the merging of Southern and Northern women's health groups resulted in a powerful transnational movement, with a collective oppositional identity based on shared solidarity in campaigns for reproductive rights and against state coercion in reproductive matters. It focuses on the ways in which the movement framed issues of rights and safety and pointed to the possible abuse potential of two new longer-acting contraceptive technologies, Norplant and the anti-fertility vaccines. The contestations by women's health advocates resulted in the emergence of a strong commitment among scientists to involve women's health advocates in the development and introduction of new contraceptive technologies. By engaging in the construction of safety and efficacy claims, and by outlining conditions for the introduction of the new technologies (so-called introduction scripts) women's health advocates were able to reinscribe the technologies with representations of bodily integrity and reproductive rights, rather than population control. I argue that a split within the women's health movement on the need to ban the new technologies did not weaken its impact, but, in fact, enhanced this success. I describe, in detailed case studies on the Norplant and Anti-fertility vaccine controversies, how both strands of women's health advocacy claim to be able to represent the interest of users, but that their representations of users differ. The 'no-to-Norplant' and 'no-to-anti-fertility' vaccines strands see users as victims of a state-led medical establishment enabled power, which is inscribed in the technology. The more moderate strand of activism argue that women's interests and needs differ from one setting to another, and that they are best met by making available to women a range of contraceptive options which allow for a free and informed choice.

In this article, the effects of Implanon implant use on thyroid and adrenal function was compared with those of Norplant implants. In this 2-year open randomized study of 80 implant acceptors, we found that both implants may induce minimal changes in thyroid hormones and cortisol levels, possibly secondary to alterations in the respective binding globulins in the serum. These alterations in thyroid and adrenal function would have no clinical significance in healthy women. In the Norplant group, sex hormone-binding globulin levels decreased, whereas increased levels were found in the Implanon users at the end of 2 years. These findings lend support to the fact that etonogestrel, released from Implanon implants, is significantly less androgenic than levonorgestrel, released from the Norplant implants.

Plasma concentrations of cholesterol, HDL-cholesterol, and levonorgestrel were determined in two groups of women using levonorgestrel-releasing subdermal implants. One group used six capsules (NORPLANT)*; the other six covered rods. Plasma concentrations of levonorgestrel among NORPLANT users averaged 700 pg/ml in the first two weeks of use, decreased to 300 pg/ml at 8 weeks, and to about 230 pg/ml by 50 weeks. Concentrations among covered rod users were 1.4 to 1.7 times higher at comparable time periods. Total serum cholesterol and HDL-cholesterol were decreased as compared with controls at all sampling intervals during the 114 weeks of the trial, although the differences did not meet tests of significance at all time periods. Decreases during the test period were of the order of 10 percent, except for total cholesterol among covered rod users where the decrease was less. Cholesterol to HDL-cholesterol ratios did not differ significantly from control values at any sampling period.

A comparison of the effects of NORPLANT capsules and NORPLANT-2 rods on liver function, lipid and carbohydrate metabolism is presented. The results indicate that the effects of both these long acting progestogen-containing subdermal implant systems are similar and comparable. With respect to liver function, possible hepatocellular dysfunction is indicated as evidenced by a significant rise in serum bilirubin and a significant fall in total protein and globulin. As regards to lipid metabolism, there appears to be no cardiovascular risk in both groups. The effects of NORPLANT on carbohydrate metabolism is not of any clinical significance.

The pathogenesis of irregular endometrial bleeding, the main reason for stopping contraception with progestins only, is unknown. Based on the recent reappraisal of the mechanisms of menstrual bleeding, we hypothesized that matrix metalloproteinases initiate this disorder. Volunteers upon Norplant treatment provided endometrial biopsies at the start of a bleeding episode and during nonbleeding intervals. Focal stromal breakdown, collagen fiber lysis, and collagenase-1 messenger ribonucleic acid were evidenced in most bleeding endometria, but never in the nonbleeding ones. In the breaking down areas, immunolabeling for gelatinase A was strongly increased, and that of progesterone and estrogen receptors was decreased. Explants from bleeding endometria produced high collagenase and gelatinase activities, whereas release from nonbleeding endometria was negligible. Bleeding endometria released more latent and active forms of collagenase-1 and active gelatinases A and B, but less tissue inhibitor of metalloproteinases-1, than nonbleeding endometria. Collagenase-1 release closely correlated with that of interleukin-1alpha. In contrast, N:-acetyl-beta-hexosaminidase and tissue inhibitor of metalloproteinases-2 were similarly released in both groups. Thus, endometrial bleeding occurs together with focal stromal breakdown, collagen lysis, expression and activation of several matrix metalloproteinases, and decreased production of tissue inhibitor of metalloproteinases-1. These results may lead to new pharmacological treatment of this common medical problem.

Bleeding problems can be one of the major reasons for women to discontinue the use of hormonal contraceptives. Causes of endometrial bleeding can include disturbances in endometrial regeneration and angiogenesis. Endothelial cells migrate and proliferate rapidly as part of the angiogenic process under the influence of appropriate stimuli. The aim of this study is to investigate the production of endothelial cell migratory signals by endometrial explants from women receiving Norplant and to compare it to that of those with a normal menstrual cycle. The subjects were selected from Norplant users with an exposure of 3-9 months. The endothelial cell migratory signal production was assayed using the Folkman method (1989), modified by Rogers (1992). Blood serum concentrations of oestradiol, progesterone and sex hormone binding globulin were monitored for 2 weeks prior to endometrial biopsy. Endothelial cell migration toward endometrial explants of 30 women as control and 46 Norplant acceptors was assayed. The results showed that endothelial cell migratory activity toward endometrial explants from the control group was significantly higher than toward those from Norplant acceptors (z = 3.89, P < 0.001). There were no differences between endometrial endothelial cell migratory activities in Norplant acceptors with bleeding or without bleeding problems.