Metabolic effects of implantable steroid contraceptives for women

The metabolic impact of progestin-only contraceptives is less than that of combined oral contraceptives. Subdermal contraceptive implant systems that provide a sustained release of low levels of progestins are now becoming widely available. This review evaluates the metabolic effects of currently available products that release the progestins levonorgestrel (Norplant, Jadelle, and their Chinese equivalents); etonogestrel (Implanon); nomegestrol acetate (Uniplant); and Nestorone, formally called ST-1435 (Nestorone implant/Elcometrine). Data on liver, kidney, and renal function; carbohydrates and insulin release; hemostasis; blood pressure; and lipids are considered. The metabolic effects reported for these methods as a whole were minimal. Any changes were generally within the normal range for the populations studied and, therefore, are unlikely to be of clinical significance. However, all published studies have been conducted in healthy populations of women. To inform clinical practice, the field would be well served to have additional empiric data from well-designed, well-implemented, and well-reported trials in women who are deemed to be at elevated risk for certain diseases including cardiovascular disease and diabetes.     

Implantable contraceptives for women: effectiveness, discontinuation rates, return of fertility, and outcome of pregnancies

Progestogen-only contraceptive implants are highly effective. In most studies, 5-year cumulative pregnancy rates are less than 1.5/100 women for Norplant and Norplant II. No study has yet reported any failures with Implanon. Weight over 70 kg and age at insertion under 25 years both increase the failure rate of Norplant and Norplant II; however, data are as yet lacking for Implanon. The effectiveness of other progestogen-only implants for which there are as yet few data are unlikely to be any different. Continuation rates are high compared with other hormonal methods and with the intrauterine device. In most cohorts at least 35% of women, and often many more, are still using Norplant by the end of 5 years. Rates vary according to a number of factors, including population studied, age, and parity. Menstrual disturbance is by far the most common reason for discontinuation, with headache, acne, weight gain, and desire for pregnancy accounting for other common reasons for implant removal. Fertility returns rapidly following implant removal, and pregnancy rates (76-100% 1 year after removal) are usually no different from those following discontinuation of any other contraceptive method. There is no increase in the risk of ectopic pregnancy, fetal malformation, or impaired infant health in pregnancies conceived either during implant use or after removal.     

A randomized multicenter study comparing the efficacy and bleeding pattern of a single-rod (Implanon) and a six-capsule (Norplant) hormonal contraceptive implant.

To compare the contraceptive efficacy, tolerability, and bleeding patterns, 200 healthy female volunteers received, in an open, comparative, randomized, multicenter study in China, either a single-rod (Implanon) or a six-capsule (Norplant) contraceptive implant for 2 years with an optional extension of up to 4 years. Women were exposed to Implanon for 341.6 woman-years and Norplant for 329.1 woman-years. There were no pregnancies during the study. Per 90-day reference period, the median number of bleeding/spotting days with Implanon decreased from 33.5 in the first period to 19.0-21.5 days in the last year. Similarly, with Norplant, the median number of bleeding/spotting days decreased from 34.5 to 18.0-23.0 days, respectively. The number of bleeding/spotting episodes during year 1 was 2.0 per 90-day reference period with Implanon and 3.0 per period with Norplant (p < 0.05 for periods 1-4). For the remaining 90-day periods, there was no statistical difference between the two groups. In general, there was less frequent bleeding with Implanon compared with Norplant, whereas the incidences of amenorrhea and infrequent bleeding were higher with Implanon than with Norplant. The mean overall incidence of prolonged bleeding fell markedly during the study, from 66.0% in reference period 1 to 27.3% in period 16 with Implanon and from 69.0% to 21.7% with Norplant, respectively. The most common adverse events were related to disturbed bleeding patterns, which were also the major reasons for discontinuation (Implanon n = 8; Norplant n = 14). Normal menses returned in almost all subjects within 3 months after removal of the implants. Implanon was inserted in a mean time of 0.61 min and Norplant in 3.90 min (p < 0.001). Similarly, the mean time required to remove the implant was significantly shorter for Implanon than for Norplant (2.18 min vs 11.25 min, p < 0.001). The maximum time required for removal of the implant was 10 min for the Implanon group and 60 min for the Norplant group. In both groups, blood pressure and hemoglobin were not affected, whereas body weight tended to increase. It can be concluded that both contraceptive systems demonstrated excellent contraceptive efficacy and were well tolerated. Compared with Norplant, there was less frequent bleeding with Implanon, whereas the incidence of infrequent bleeding and amenorrhea was higher. Implanon was significantly quicker to insert and to remove than was the multiple capsule system.     

Levonorgestrel concentrations in maternal and infant serum during use of subdermal levonorgestrel contraceptive implants, Norplant, by nursing mothers

The transfer of levonorgestrel to infants was studied in 42 lactating women in whom the contraceptive subdermal implants, Norplant, were inserted 30 to 40 days postpartum. The women breastfed their infants for one year. Simultaneous mother and infant blood samples were taken once during the year. The levonorgestrel serum concentrations were measured by radioimmunoassay. During the first postinsertion month, the levonorgestrel concentration in the infants serum amounted, on the average, to 5% of the maternal concentration. Thereafter, the ratio ranged from 8 to 13%. The implications of this finding are discussed.     

Implanon contraceptive implants: effects on carbohydrate metabolism

The objective of the study was to assess the possible differences in effects of Implanon and Norplant implants on carbohydrate metabolism. This is a 2-year open randomized study of 80 implant (Implanon and Norplant) acceptors. Oral glucose tolerance test (OGTT) was performed before implant insertion and at 6, 12, and 24 months after implant insertion. Glycosylated hemoglobin A(1)C was measured in fasting samples and plasma samples during OGTT were tested for glucose and insulin levels. There was a significant increase in the area under the curve for both glucose and insulin during OGTT within each group with increasing duration of use. However, there was no significant change in the fasting plasma glucose values. There was no significant difference in the carbohydrate parameters between the two groups during implant use, except for a minimal but statistically significant rise in fasting glycosylated hemoglobin A(1)C levels at 24 months in the Implanon group. Both implants appear to induce mild insulin resistance but no significant change in serum glucose levels. These alterations in carbohydrate metabolism should have no clinical significance in healthy women.     

Mechanisms that explain the contraceptive action of progestin implants for women

Four different contraceptive implants for women, in the form of capsules or covered rods, that release either one of the synthetic progestins levonorgestrel, etonogestrel, Nestorone, or Elcometrine and nomegestrol acetate were considered. These progestins act by binding to their receptors located in diverse target cells, which are distributed along the hypothalamic-pituitary-gonadal-genital tract axis. These implants differ in the extent to which each one interferes with various steps of the reproductive process and in the intensity with which each one affects the same process along its effective life, but they have in common the ability to interfere with several key processes required for gamete encounter and fertilization. The steps they interfere with most are the ovulatory process, through partial or complete inhibition of the gonadotropin surge, and by changing the quality of cervical mucus; they restrict or suppress the access of fertile spermatozoa to the site of fertilization. Changes in endometrial development also occur, but this contribution to the contraceptive action is difficult to determine at the present time.     

Effect of Implanon use on selected parameters of thyroid and adrenal function

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.     

Enhanced metabolism of levonorgestrel during phenytoin treatment in a woman with Norplant implants

A 26-year-old woman, treated with phenytoin for 10 years because of epilepsy, had Norplant subdermal implants inserted after a legal abortion. She became pregnant again after nine months of Norplant use. Her plasma levonorgestrel (LNG) levels were followed during one month during phenytoin treatment and then later during one month after discontinuation of phenytoin. During phenytoin treatment, plasma LNG levels were markedly below the levels found in healthy women with Norplant. There was a pronounced, statistically significant increase in plasma LNG levels after discontinuation of phenytoin. The plasma levels of sex hormone binding globulin were markedly above those found in normal healthy women during treatment with phenytoin and decreased significantly after cessation of phenytoin. The effects on the pharmacokinetics of LNG were reflected by effects on the menstrual cycle. During phenytoin treatment, the woman had regular ovulatory menstrual cycles. After cessation of phenytoin, her cycles became irregular and during the study period of one month, no signs of ovulation were found. It is concluded that treatment with phenytoin during use of Norplant subdermal implants enhances the metabolism of LNG to an extent where the contraceptive efficacy is endangered.     

Progestin implants for female contraception

Four different implants, in the form of capsules or covered rods, that release one of the synthetic progestins levonorgestrel, etonogestrel, Nestorone, or Elcometrine and nomegestrol acetate were reviewed. Biocompatible polymers or copolymers of polydimethyl/polymethylvinyl-siloxanes or ethylvinylacetate are used to hold the steroid crystals and to control the rate of release. Once inserted under the skin, these implants release the corresponding steroid continuously over prolonged periods, a process that can be readily interrupted by implant removal. During long-term use of the implant, the released steroid circulates in blood at a fairly stable level. The physical characteristics of the implants, including drug contents and rate of release, serum levels of the progestin during use, and the duration of their effective life are described. Total steroid loads vary in the range of 50 mg to 216 mg; average release rates are in the range of 30-100 ug/day, and effective lives from 6 months to 7 years.     

Fertility regulation in nursing women: VII. Influence of NORPLANT levonorgestrel implants upon lactation and infant growth

The objective of this study was to test the influence of NORPLANT implants upon lactation and infant growth. The results obtained during the first postpartum year are reported. One-hundred women were enrolled in the implant group. The control group was formed by 100 women who received a Copper T IUD. Treatments were administered at day 55 +/- 3. At admission all subjects were in exclusive breastfeeding with an adequate weight increase of the infant. No significant differences were found between the treated and control groups in the percentage of women in full nursing at different postpartum intervals, except for the 12th month postpartum where a lower percentage of cases from the NORPLANT group was in the full nursing category. No difference was found in the time of weaning. The infants showed a normal weight gain rate in both groups although the girls from the NORPLANT group showed a significantly lower daily weight increase during the 4th month than the girls from the IUD group. No pregnancies were diagnosed. No women asked for implant removal during the first year. No serious side effects related to treatment were detected. Bleeding irregularities were rare during breastfeeding which is in contrast with what occurs in non-nursing women treated with NORPLANT implants. Levonorgestrel concentrations found in milk were variable and individual values ranged from 23 to 311 pg/ml. The dose received by the infant can be estimated around 15 to 18 ng/Kg/day during the first month of treatment when the higher plasma values of levonorgestrel are observed. These levels is conjunction with the clinical observations reported here minimize the potential problems associated with levonorgestrel transference through maternal milk. Nevertheless, long-term studies are required to settle this matter and until more information is available, NORPLANT implant use in lactating women should be limited to cases who require a highly effective contraceptive method and where non-hormonal methods of similar effectiveness are contraindicated or unacceptable.     

Ovarian cysts in users of Implanon and Jadelle subdermal contraceptive implants

OBJECTIVE: To evaluate the prevalence of ovarian cysts in users of two contraceptive implants compared to users of intrauterine contraceptive (IUC). MATERIALS AND METHODS: A total of 344 women were enrolled at 3 months of use of the etonogestrel-releasing implant (Implanon), the levonorgestrel-releasing implant (Jadelle) or the TCu380A IUC. Bimanual pelvic examination and vaginal ultrasound were performed during routine 3-, 6- and 12-month visits of asymptomatic women. Women with ovarian cysts (or enlarged ovarian follicles > or = 25 mm) were assessed weekly until disappearance or reduction of the image [including estradiol (E2) and progesterone (P) measurement], and women with no ovarian enlargement underwent the same evaluation for the same period of time. RESULTS: Ovarian cysts were detected in 5.2%, 13.0% and 1.9% of users of Implanon, Jadelle and IUC, respectively, at 3 months. At 6 months of use, prevalence was 7.2%, 8.0% and 2.1%, whereas 12-month rates were 26.7%, 14.6% and 1.2% in the three groups, respectively. E2 levels were significantly higher among users with ovarian cysts than controls. The time until disappearance of the ovarian cyst was similar in all three groups. There were more cases of menorrhagia in users of implants who had ovarian cysts than in those with no ovarian enlargement. CONCLUSIONS: The finding of ovarian cysts or enlarged ovarian follicles during the first year of use of Implanon and Jadelle implants is common and transient and should not be interpreted as a pathologic ovarian cyst. No further medical interventions are necessary.     

Norplant contraceptive implants: rods versus capsules

Norplant contraceptive implants are silastic implants containing levonorgestrel. When placed subcutaneously in the medial aspect of the upper arm, they release low levels of levonorgestrel in a constant manner over an extended period of time. Comparative studies of two silastic rods versus six capsules containing levonorgestrel were studied in 250 subjects for 4,464 months of use. Only one pregnancy occurred during the study. Side effect patterns were similar in both groups; the major side effect being irregular uterine bleeding. The bleeding, however, was well tolerated by subjects in both groups and discontinuation rate was very low. The two-rod system offers the advantages of easier insertion technique and shorter insertion time as well as ease of removal as compared to the six-capsule system. Norplant contraceptive implants offer a highly effective means of contraception which is particularly suited for women who are concerned about failure and compliance with oral contraceptives. This type of contraception should become well accepted, not only in underdeveloped countries, but in developed countries as well.     

WHO 86925 Norplant上市后监测(中国部分)

本课题研究目的是对Norplant皮下埋植剂潜在副作用进行监测,以进一步证实其安全性。对使用Norplant和IUD或绝育术的妇女进行比较随访研究。每半年随访一次,详细记录所有健康情况,共随访5年。随访率达99.9％。结果:Norplant组及对照组IUD和绝育术的5年继续使用率分别为76.25、80.89、98.10/100使用者。Norplant的5年累计妊娠率为0.6/100使用者,远低于IUD的8.11/100使用者,宫外孕发生率为0.46/1000妇女年,低于IUD的1.24/1000妇女年,但宫外孕和妊娠之比在Norplant组为31.6:100,远高于IUD的6.7:100,如发生妊娠,要警惕宫外孕的可能。月经问题是Norplant的主要终止使用原因,但使用5年者,其血红蛋白均值上升,和接收时相比P<0.001,而IUD使用5年者,其血红蛋白均值下降,和接收时相比P<0.01。在观察5年中胆囊炎胆石症、纤维囊性乳腺病在Norplant使用者中的发病率高于对照组,P<0.05～0.001,但未发现重大健康问题。Norplant使用5年是安全的。     

Effect of etonogestrel subdermal contraceptive implant (Implanon) on liver function tests -- a randomized comparative study with Norplant implants

OBJECTIVE: The study aimed to assess the possible differences in effects of Implanon and Norplant implants on liver function over 2 years of use. METHODS: This is a 2-year open randomized study of 80 implant (Implanon and Norplant) acceptors. Selected parameters of liver function were tested in the serum before implant insertion and at 6, 12 and 24 months after implant insertion. RESULTS: In both the implant groups, the mean total and unconjugated bilirubin and the gamma-glutaryl transferase levels were significantly raised during implant use. For none of the subjects, at any sampling period, did the levels exceed the normal range in our population. There was no significant elevation of any other liver enzymes in either group. CONCLUSION: It appears that there may be mild hepatocellular dysfunction associated with the use of both Implanon and Norplant, which is possibly of no clinical significance to the healthy acceptor.     

NorplantR contraceptive subdermal implants: Two-year experience in Singapore

Norplant contraceptive implants are Silastic containing levonorgestrel implants. This study describes our two-year experience with 100 acceptors of Norplant implants in Singapore. No pregnancies occurred during the first two years of use. Desire for planned pregnancy and disruption of menstrual rhythm were the two main reasons for twenty implant removals during the two years. The continuation rate at the end of two years was 79%. The post-removal conception rate in women desiring pregnancy was 90% at the end of one year. It thus appears that the Norplant contraceptive system offers a highly effective, acceptable, reversible and safe method of contraception.     

Use of Norplant implants in a New York City clinic population

Two-hundred-eight women attending family planning clinics in New York City who received the Norplant contraceptive system during the first sixteen months of Norplant implants insertions were evaluated. Within this clinic population, Norplant implants were a popular contraceptive choice and were removed from 64 of the 208 recipients. Reasons for removal included bleeding, weight gain, and headache, and were consistent with those found in the clinical trials. Prior satisfaction with oral contraceptives did not predict success or failure with Norplant implants. The rate of follow-up visits to the family planning clinics was low. However, evidence exists that these women did not lose contact with the medical center and continued to receive health care.     

Nonpalpable ultrasonographically not detectable Implanon rods can be localized by magnetic resonance imaging

Recently, the contraceptive implant Implanon has been introduced in several European countries. In comparison to the six-capsule preparation Norplant, the removal of this single-rod system should be associated with less complications. However, the removal of nonpalpable Implanon rods can be difficult because the implant is not always visible with ultrasound. The aim of this study was to find a radiologic method for the localization of Implanon implants that are nonpalpable and can not be detected by ultrasound. X-ray, ultrasound, computed tomography, and magnetic resonance imaging (MRI) were investigated as methods to localize Implanon in a pig chest preparation and in a woman with a nonpalpable implant. The implant in the woman could be localized unequivocally only by MRI. We conclude that MRI is the best method for the unequivocal localization of nonpalpable, ultrasonographically not detectable Implanon rods. To avoid unnecessary scar tissue formation, it may be appropriate to defer surgery for the removal until definitive localization.     

A multicenter comparative study on the efficacy, safety, and acceptability of the contraceptive subdermal implants Norplant and Norplant-II

In order to assess efficacy, safety, and acceptability of the contraceptive subdermal implants Norplant^® and Norplant^®-II in Mexican women, a comparative phase III clinical trial was undertaken in eight clinics across the country. The study involved 1052 women who were followed-up trimonthly for three years. Cumulative pregnancy rates were 0.29% and 0.34% for Norplant and Norplant-II implants, respectively. Similar overall cumulative discontinuation rates were observed at three years: 50.38% for Norplant capsules, and 50.44% for Norplant-II rods. The main method-related reason for termination was endometrial bleeding irregularity which led to discontinuation rates of 11.94% and 11.62% for Norplant and Norplant-II contraceptive systems, respectively. In 15,279 woman-months of experience accumulated with Norplant implants and 14,092 with Norplant-II implants, there were few adverse events reported. No difference was found between the two groups in either difficulty for implants placement and removal or women's discomfort, even though the time required for insertion and removal of Norplant capsules was longer than for Norplant-II rods. It is concluded that during the first three years of use, both implants systems are equally effective, safe, and acceptable.     

The use of hormonal contraception among women taking anticonvulsant therapy

Background

Drug interactions between hormonal contraceptives and anticonvulsants, resulting in reduced contraceptive effectiveness and/or increased seizure activity, have been published.

Study design

We conducted a systematic review, searching PUBMED and The Cochrane Library for articles in any language on use of hormonal contraceptive methods among women taking anticonvulsant therapy from 1966 through 3 May 2010. Forty-three articles were identified and evaluated.

Results

Evidence suggests drug interactions occur when combined oral contraceptives (COCs), the levonorgestrel implant (Norplant), or the etonogestrel implant (Implanon) are used concomitantly with carbamazepine, phenobarbital, phenytoin, topiramate or lamotrigine. Significant drug interactions were not observed during sodium valproate intake and COC use nor among women using progestogen-only contraceptives and taking lamotrigine.

Conclusions

To avoid contraceptive failure or increased seizure activity, women with epilepsy should be offered contraceptive methods that do not interact with anticonvulsant medication.     

A five-year clinical evaluation of NORPLANT contraceptive subdermal implants in Bangladeshi acceptors

A non-comparative study of the Norplant contraceptive subdermal implant system was conducted in Dhaka, Bangladesh. The study was designed to evaluate the contraceptive efficacy, safety and overall acceptability of Norplant implants. Six hundred women were enrolled in the clinical trial, which began in 1985 at three study sites. Follow-up visits were scheduled at 1, 3, and 6 months after Norplant implant insertion, and every six months thereafter until removal or at the end of five years. There were no post-insertion pregnancies during Norplant implant use in this study. After five years of Norplant implant use, there was no clinically significant change in body weight, systolic or diastolic blood pressure. Less than 3% of the women ever reported having any significant medical problems such as migraine, respiratory or cardiac problems during the study. The gross cumulative continuation rate was 41.2 per 100 women at the end of five years. The two most frequently reported reasons for discontinuation during the study were menstrual problems and desired pregnancy. Of the women who completed the five-year user satisfaction questionnaire, the majority of the women (86.3%) planned to continue using contraception after study completion. Of these women, approximately one-third said they planned to use another Norplant set. The findings presented suggest that the Norplant system is a highly effective, safe and acceptable method among Bangladeshi women.