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PubMed1984

[Progress in oral contraception. Advantages of a levonorgestrel-containing 3-stage preparation over low-dose levonorgestrel and desogestrel containing monophasic combination preparations].

The three-phase preparation, which contains levonorgestrel, has a number of advantages compared to the traditional monophase combination preparations. With the same contraceptive reliability its cycle stability is very much better than the monophase preparations, which are 40% high dosed in the progestin proportion (levonorgestrel and desogestrel). The dose relations of the new preparation agree with the most recent scientific knowledge on the metabolism aspects of hormonal contraceptives. The hormone dosage in the various phases of the menstrual cycle is largely adapted to the plasma level course of beta-oestradiol and progesterone in the corresponding phases of the normal cycle.

Clinical Trials as Topic↗
PubMed1994

Pharmacokinetics of levonorgestrel and ethinylestradiol in 14 women during three months of treatment with a tri-step combination oral contraceptive: serum protein binding of levonorgestrel and influence of treatment on free and total testosterone levels in the serum.

The pharmacokinetics of levonorgestrel (LNG) and ethinylestradiol (EE2) were determined in 14 healthy women (age 18 to 27 years) during a treatment period of three months with a tri-step combination oral contraceptive (Triquilar). Prior to this treatment period, the same women received a single administration of a coated tablet containing 0.125 mg LNG together with 0.03 mg EE2. There was a washout phase of one week between both treatments. Following single dose administration, a mean terminal half-life of 22 h was observed for LNG. The total clearance was 1.0 ml x min-1 x kg-1 and the volume of distribution was 128 l. During a treatment cycle, LNG levels in the serum accumulated by a factor of about four as compared to single dose administration. Steady-state drug levels were reached during the second half of each cycle. As compared to single dose administration, the following changes were observed for LNG at the end of treatment cycles one and three: reduced total (0.5 ml x min-1 x kg-1) and free clearance (50 ml x min-1 x kg-1) and a reduced volume of distribution (52 l). A concomitant increase in the SHBG concentrations by a factor of two as compared to pretreatment values was observed during treatment and appeared to be mainly responsible for the changes in the pharmacokinetics of LNG. Marked changes were also seen for the serum protein binding of LNG. After single dose administration, the free fraction of LNG was 1.4% and the fractions bound to SHBG and albumin were 55.0% and 43.6%, respectively. At the end of cycle one, the free fraction was only 1.0% and the fractions bound to SHBG and albumin were 69.4% and 30.0%, respectively. There was no difference in corresponding pharmacokinetic parameters and in the serum protein binding of LNG at the end of cycles one and three. On the last day of treatment cycles one and three, the AUC(0-4h) values of EE2 were 331.2 and 369.6 pg x ml-1 x h, respectively, which corresponds to an about 11-24% increase as compared to single dose administration, where an AUC(0-4h) value of 298.3 pg x ml-1 x h was found. Total and free testosterone concentrations decreased during treatment cycles one and three by about 41% and 55%, respectively, compared with the corresponding values measured prior to treatment.

Administration, Oral↗
PubMed1992

Pharmacokinetics of levonorgestrel in 12 women who received a single oral dose of 0.15 mg levonorgestrel and, after a washout phase, the same dose during one treatment cycle.

The pharmacokinetics of levonorgestrel (LNG) was determined in 12 healthy women (age 21 to 33 years), following single dose administration of 0.15 mg LNG. The same preparation was also administered during one treatment cycle after a washout phase of 1 week. After single dose administration, maximum concentrations of LNG in the serum were 4.3 +/- 1.3 ng/ml. Post maximum drug levels declined biphasically with half-lives of 0.6 +/- 0.2 h and 13.9 +/- 3.2 h, respectively. The clearance was calculated to be 1.5 +/- 0.6 ml x min-1 x kg-1. The free fraction of LNG was 1.1 +/- 0.1% and the fractions bound to SHBG and albumin were 61.8 +/- 6.7% and 37.1 +/- 6.7%, respectively. There was a gradual decrease in serum trough levels of LNG from about 0.5 to 0.3 ng/ml during the cycle, and a concomitant decrease in SHBG concentrations in the serum by about 50%. Serum protein binding of LNG changed markedly during the treatment cycle. The free fraction increased to a value of 1.7 +/- 0.3%, the SHBG-bound fraction decreased to 42.0 +/- 11.4% and the albumin-bound fraction increased to 56.4 +/- 11.2%. Total serum clearance increased during the same time period from a mean value of 1.5 to about 2.5 ml x min-1 x kg-1. The clearance of unbound LNG, however, remained unchanged. An examination of the free LNG concentrations revealed the same time course of LNG trough levels during the cycle as the simulated curve. This was derived from the pharmacokinetic parameters which were obtained after single dose administration. Thus, the present study showed that the pharmacokinetics of LNG can be fully explained on the basis of single dose pharmacokinetics and the changes in serum protein binding which were caused by a reduction of SHBG levels in the serum during chronic treatment with LNG.

Administration, Oral↗
PubMed2005

A 1-year study to compare the hemostatic effects of oral contraceptive containing 20 microg of ethinylestradiol and 100 microg of levonorgestrel with 30 microg of ethinylestradiol and 100 microg of levonorgestrel.

OBJECTIVES: To comparatively evaluate the impact of a balanced one-third dose-reduced oral contraceptive on hemostatic variables. METHODS: In an open-label, randomized study, a dose-reduced oral contraceptive containing 20 microg of ethinylestradiol (EE) and 100 microg of levonorgestrel (LNG) was compared with a reference preparation containing 30 microg of EE and 150 microg of LNG. One-year data were obtained from 48 volunteers. RESULTS: The direction and magnitude of the changes (increase or decrease) in most of the hemostatic variables were similar in both treatment groups. The majority of changes of all investigated variables remained within the reference ranges of variation. The procoagulatory variables increased to some extent from baseline to treatment cycle 13, while the anticoagulatory variables slightly decreased. In particular, thrombin turnover measured by prothrombin fragments 1+2 increased during treatment by 35% in the 20 microg of EE group and by 38% in the 30 microg of EE group. Statistically significant differences between the two treatment groups were found only for TAT. For the profibrinolytic variables, plasminogen was increased by 42% (20 microg of EE) and 49% (30 microg of EE). While the plasma levels of tPA antigen were reduced during treatment, the levels of its activity were increased by 54% (20 microg of EE) and 20% (30 microg of EE). For PAI, both antigen and activity were decreased, somewhat more pronounced with 20 microg of EE. D-Dimer remained virtually unchanged. Finally, the median FbDP levels were elevated by 30% (20 microg of EE) and 38% (30 microg of EE).

Adult↗
PubMed1994

[Pharmacokinetics of levonorgestrel after a single dose of biodegradable microspheres containing levonorgestrel in rats].

Pharmacokinetics of levonorgestrel (LNG) in the form of injectable microspheres made of biodegradable co-polymer of polylactic acid and polyglycolic acid(9: 1 PLGA) that contained 17.76% LNG, were tested in rats. Rats were given a single intramuscular injection (im) of LNG microspheres at doses of 20.4, 41.1 and 83.3 mg.kg-1. Six rats were treated with a single im of LNG microcrystals at dose of 35.0 mg.kg-1. Plasma samples obtained before injection and at various time after injection were analyzed for LNG by RIA method. Peak plasma LNG level of 67.66 nmol.L-1 was obtained 4.88 h after im of LNG microcrystals, T1/2 = 5.78 d, MRT = 10.16 d and T < 0.32 nmol.L-1 = 41.50 d. Plasma LNG levels among rats after im of three different doses of LNG microspheres showed similar biphasic changes. Cmax1 (the first phase) were 15.19, 33.61 and 38.55 nmol.L-1; Tp1 were 6, 4.67 and 4.33h; Ctrough were 1.21, 4.36 and 9.06 nmol.L-1; Ttrough were 55, 53.67 and 54.83 d; Cmax2 (the second phase) were 3.80, 9.48 and 19.68 nmol.L-1; Tp2 were 100.49, 102.21 and 89.27 d; AUC were 440.27, 1082.82 and 1931.47 nmol.d.L-1; MRT were 69.23, 65.12 and 63.25 d; T < 0.32 nmol.L-1 were 167.81, 169.73 and 167.23 d after im of LNG microspheres in doses of 20.4, 41.1 and 83.3 mg (LNG).kg-1, respectively. Cmax1, Ctrough, Cmax2 and AUC showed significantly positive correlation with LNG dose, while Tp1, Tp2, Ttrough, MRT and T < 0.32 nmol.L-1 did not.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Contraceptives containing desogestrel or levonorgestrel have different effects on serum lipoproteins and post-heparin plasma lipase activities.

OBJECTIVE: We examined the effects of mono and polyphasic oral contraceptives containing desogestrel or levonorgestrel on serum lipoproteins, sex hormone binding globulin and post-heparin plasma lipase activities. DESIGN: The women took either desogestrel or levonorgestrel during the first menstrual cycle on days 15-28. They then received monophasic ethinyloestradiol plus either desogestrel or levonorgestrel for three cycles. After this, the women took sequential pills containing ethinyloestradiol plus either desogestrel or levonorgestrel for the three following cycles. Fasting blood samples were drawn pretreatment and at the end of each treatment. PATIENTS: The study group consisted of 30 apparently healthy women, aged 18-35. They were randomly divided into desogestrel and levonorgestrel groups, each consisting of 15 women. MEASUREMENTS: Cholesterol, triglyceride and phospholipids were determined in whole serum and in all lipoprotein fractions (following isolation of lipoproteins by ultracentrifugation). Plasma apolipoprotein A-I concentration, post-heparin plasma lipase activities and serum sex hormone binding globulin were also measured. RESULTS: Desogestrel (150 micrograms/day) did not change serum total triglyceride concentration, whereas levonorgestrel (150 micrograms/day) decreased it. Except for monophasic ethinyloestradiol plus levonorgestrel, the oestrogen-containing combinations increased serum triglyceride level. Low density lipoprotein (LDL) cholesterol remained stable with all treatments, but the cholesterol/triglyceride ratio of LDL decreased during all combinations with ethinyloestradiol. Levonorgestrel reduced total high density lipoprotein (HDL) cholesterol and both progestins reduced HDL2 cholesterol concentration. Addition of ethinyloestradiol reversed this change in the desogestrel but not in the levonorgestrel group. The polyphasic ethinyloestradiol plus levonorgestrel combination did not change total HDL cholesterol. Hepatic lipase was activated with either progestin when administered alone but its activity was suppressed below the baseline level when ethinyloestradiol was added. Conversely, both progestins suppressed sex hormone binding globulin levels, but addition of ethinyloestradiol caused marked increases above baseline. These increases were greater in women taking desogestrel than in those taking levonorgestrel. No treatment affected lipoprotein lipase activity significantly. CONCLUSIONS: Monophasic or polyphasic combinations of ethinyloestradiol and desogestrel do not have deleterious effects on serum lipoproteins. If levonorgestrel is used as the progestin component, polyphasic ethinyloestradiol plus levonorgestrel appears more favourable than monophasic ethinyloestradiol plus levonorgestrel.

Adolescent↗
PubMed1994

Systemic availability of levonorgestrel after single oral administration of a norgestimate-containing combination oral contraceptive to 12 young women.

Norgestimate is a novel progestin which undergoes both in vivo and in vitro metabolic conversions to a number of metabolites, of which the most important are levonorgestrel acetate, levonorgestrel oxime and levonorgestrel itself. It has been claimed that the progestogenic activity of norgestimate in clinical studies is almost exclusively based on the parent drug and its major metabolite, levonorgestrel oxime, and that levonorgestrel does not make an important contribution. However, to date, no data on the presence of levonorgestrel in the serum of women who have received oral doses of norgestimate have been presented. In the present study, 12 young female volunteers received single oral doses of 250 micrograms levonorgestrel in combination with 50 micrograms ethinylestradiol and 250 micrograms norgestimate in combination with 35 micrograms ethinylestradiol in an open, randomized, intraindividual comparison. Blood samples were taken at regular time intervals after each treatment, and the serum samples were analyzed for their content of levonorgestrel. Basic pharmacokinetic parameters of levonorgestrel were calculated and from the ratio of the AUC values obtained after both administrations, the bioavailability of norgestimate-derived levonorgestrel was calculated. About 22 +/- 6% of the dose of norgestimate administered became systemically available as levonorgestrel. Thus, it was concluded that levonorgestrel is a major metabolite of orally administered norgestimate, and that at least part of the pharmacologic activity of norgestimate in women is due to the presence of levonorgestrel.

Adolescent↗
PubMed2005

Pharmacokinetics and endometrial tissue levels of levonorgestrel after administration of a single 1.5-mg dose by the oral and vaginal route.

OBJECTIVE: To determine the pharmacokinetics and endometrial tissue levels of levonorgestrel when taken as a single dose of 1.5 mg either orally or vaginally by healthy women in the periovulatory phase of their menstrual cycle. DESIGN: Prospective randomized study. SETTING: Academic research institution. PATIENT(S): Thirty women with regular cycles allocated to control (n = 5), oral (n = 13), and vaginal (n = 12) groups. INTERVENTION(S): Blood samples were drawn before (0 time) and at 0.5, 1, 2, 4, 6, 8, 24, 48, and 168 hours after levonorgestrel administration. Endometrial samples were collected 24 and 168 hours after levonorgestrel administration. MAIN OUTCOME MEASURE(S): Plasma and endometrial tissue levels of levonorgestrel. RESULT(S): Plasma concentrations of levonorgestrel were significantly greater during the first 48 hours after oral administration. However, 7 days after levonorgestrel administration, the plasma levels were similar for both treatments (3-5 nmol/L). Compared with vaginal administration, oral administration resulted in higher peak plasma concentrations (Cmax 64 vs. 10.7 nmol/L), with a shorter time to reach the maximal concentrations (Tmax 1.4 vs. 6.6 hours) and with a greater AUC (509 vs. 175 nmol/L). Interestingly, the half-life of levonorgestrel was shorter after oral administration (25 hours vs. 32.6 hours). Levonorgestrel tissue concentrations were not related to the plasma levels. Levonorgestrel values tended to be higher in endometrial tissue after vaginal administration. The ratio between plasma and endometrial concentrations of levonorgestrel differed significantly between the groups. CONCLUSION(S): These data indicate that orally administered levonorgestrel achieves higher plasma levels sooner than vaginally administered levonorgestrel. However, plasma levels after vaginal administration are more sustained and were likely to be sufficient for ovarian suppression. Therefore, the vaginally administered levonorgestrel could be considered as an alternative option for emergency contraception.

Administration, Intravaginal↗
PubMed2002

Low dose mifepristone and two regimens of levonorgestrel for emergency contraception: a WHO multicentre randomised trial.

BACKGROUND: A single 10 mg dose of mifepristone, and two 0.75 mg doses of levonorgestrel 12 h apart, are effective for emergency contraception. Because no studies had compared the efficacies of both compounds, or investigated a single dose of 1.5 mg levonorgestrel, we undertook this three-arm trial. METHODS: We did a randomised, double-blind trial in 15 family-planning clinics in 10 countries. We randomly assigned 4136 healthy women with regular menstrual cycles, who requested emergency contraception within 120 h of one unprotected coitus, to one of three regimens: 10 mg single-dose mifepristone; 1.5 mg single-dose levonorgestrel; or two doses of 0.75 mg levonorgestrel given 12 h apart. The primary outcome was unintended pregnancy; other outcomes were side-effects and timing of next menstruation. Analysis was by intention to treat, but we did exclude some patients from the final analyses. FINDINGS: Of 4071 women with known outcome, pregnancy rates were 1.5% (21/1359) in those given mifepristone, 1.5% (20/1356) in those assigned single-dose levonorgestrel, and 1.8% (24/1356) in women assigned two-dose levonorgestrel. These proportions did not differ significantly (p=0.83). The relative risk of pregnancy for single-dose levonorgestrel compared with two-dose levonorgestrel was 0.83 (95% CI 0.46-1.50), and that for levonorgestrel (the two regimens combined) compared with mifepristone, 1.05 (0.63-1.76). Side-effects were mild and did not differ greatly between groups, and most women menstruated within 2 days of the expected date. Women who took levonorgestrel had earlier menses than did those who took mifepristone. INTERPRETATION: The three regimens studied are very efficacious for emergency contraception and prevent a high proportion of pregnancies if taken within 5 days of unprotected coitus. Mifepristone and levonorgestrel do not differ in efficacy. A 1.5 mg single levonorgestrel dose can substitute two 0.75 mg doses 12 h apart.

Adult↗
PubMed2001

The pharmacokinetics of 750 microg levonorgestrel following administration of one single dose or two doses at 12- or 24-h interval.

The administration of two tablets of 750 microg levonorgestrel at a 12- to 24-h interval has been shown to be a safe and effective means of emergency contraception, and Norlevo/Vikela (N/V) is a dedicated product for this indication. The aim of this study was to characterize the plasma pharmacokinetics of levonorgestrel following a single N/V tablet administration and following a second administration, 12 or 24 h after the first one in young, healthy, female volunteers under the same conditions as during clinical use. This was an open, observer-blind, randomized study with three parallel groups and three treatments performed in 24 white female volunteers randomized into three groups of eight participants, each receiving one of the following treatments: Group A, one tablet of 750 microg levonorgestrel at time -12 h and one tablet at time 0; Group B, one tablet of 750 microg levonorgestrel at time 0; Group C, one tablet of 750 microg levonorgestrel at time -24 h and one tablet at time 0. All treatments started between Day 2 and Day 6 of the menstrual cycle. Plasma levonorgestrel levels were measured at regular intervals from time 0 up to 36 h with a validated radioimmunoassay. The results of this study show that after either one single or two administrations of a tablet containing 750 microg levonorgestrel, levonorgestrel is rapidly absorbed. The absorption, distribution, and elimination profiles of levonorgestrel following the three different treatments were similar. It also indicates that 12 or 24 h after administration there remains a significant level of plasma levonorgestrel. In conclusion, this study reinforces clinical guidelines recommending that N/V tablets for emergency contraception be administered 12 to 24 h apart because levonorgestrel is present in plasma between the two administrations.

Adult↗
PubMed1998

Correlates and consequences of early removal of levonorgestrel implants among teenaged mothers.

OBJECTIVE: To determine if adolescent mothers who request early removal of levonorgestrel implants differ from those who do not in ways that might predispose them to repeated conceptions and in their concerns about adverse effects. We hypothesized that adolescent mothers who request removal of levonorgestrel implants within 2 years of insertion have more risk factors for repeated pregnancy than those who do not. METHODS: We studied the prevalence of 21 characteristics associated with repeated adolescent pregnancy and 16 adverse effects of levonorgestrel implants in 181 postpartum, adolescent levonorgestrel implant recipients, 66 (36%) of whom had the levonorgestrel implants removed within 20 months of insertion (hereafter, removers). RESULTS: Removers (n = 66) had significantly more risk factors for repeated pregnancy and reported significantly more adverse effects than did those who continued to use levonorgestrel implants (hereafter, users) (n = 115). Concerns about adverse effects rose in tandem with risk factors for repeated pregnancy (r = 0.26; P = .001) and were the most important determinant of levonorgestrel implant removal (relative risk, 9.72; 95% confidence interval, 4.62-19.49). However, the number of risk factors for repeated pregnancy was also a significant, independent predictor of levonorgestrel implant removal (relative risk, 2.34; 95% confidence interval, 1.10-4.66). Following removal, contraceptive use was poor and conception occurred rapidly; 24 (37%) of the removers conceived again within 2 years of the index delivery. CONCLUSIONS: The study hypothesis was supported. Our findings that concerns about the adverse effects of levonorgestrel implants rise in tandem with risk factors for repeated pregnancy suggest that the efficacy of counseling before and after levonorgestrel implant insertion could be improved by addressing those aspects of the user's life that undermine the motivation to use contraception.

Adolescent↗
PubMed1982

Puerperal insertion of a copper-releasing and a levonorgestrel-releasing intrauterine contraceptive device.

A copper-releasing IUD and levonorgestrel-releasing IUDs releasing 30 micrograms and 10 micrograms levonorgestrel per day were inserted six weeks after delivery in 110 volunteers. During the treatment, events and patterns of bleeding were recorded and plasma levonorgestrel concentrations were measured. The number of events in one year of follow-up was very low, four removals out of 40 in the copper-releasing IUD group and five removals out of 70 in the levonorgestrel-releasing IUD group. Bleeding and spotting was significantly more common after insertion of a levonorgestrel-releasing IUD than a copper-releasing IUD, but it was scanty and well-tolerated. After three months, levonorgestrel-releasing IUD patients had less bleeding and spotting than the copper-releasing IUD patients. No pregnancies occurred during the study period. There were two uterine perforations with a uterine sound at the insertion. In the 30-micrograms per day levonorgestrel-releasing IUD group, initially high plasma levonorgestrel concentrations reached a plateau four weeks after the insertion. In the 10-micrograms per day levonorgestrel-releasing IUD group, the plasma concentrations of levonorgestrel stabilized after the initial two weeks.

Adult↗
PubMed2004

Treatment of dysfunctional uterine bleeding: patient preferences for endometrial ablation, a levonorgestrel-releasing intrauterine device, or hysterectomy.

OBJECTIVE: To investigate patient preferences for endometrial ablation and a levonorgestrel-releasing intrauterine device (IUD) as alternatives to hysterectomy in the treatment of dysfunctional uterine bleeding. DESIGN: Comparative study based on structured interviews. SETTING: A large teaching hospital with 500 beds in the Netherlands. PATIENT(S): Ninety-six patients who were scheduled for endometrial ablation, 25 patients who were scheduled for hysterectomy, and 23 patients who were scheduled for a levonorgestrel-releasing IUD were interviewed. All of the women had dysfunctional uterine bleeding. INTERVENTION(S): Patients were asked to state their most significant complaints and their reasons for choosing a particular treatment. Subsequently, the preference for endometrial ablation and a levonorgestrel-releasing IUD as alternatives to hysterectomy was assessed during a structured interview. Women were informed about the advantages and disadvantages of all three treatment options. Patients rated their preferences according to different hypothetical success rates. The success rates after endometrial ablation and levonorgestrel-releasing IUD were varied until patients found an acceptable treatment outcome. MAIN OUTCOME MEASURE(S): Patient preference of endometrial ablation and the levonorgestrel-releasing IUD over hysterectomy. RESULT(S): The main reason for the treatment of choice differed between the three groups. Most of the patients in the hysterectomy group wanted a definite solution to their problems, whereas patients in the levonorgestrel-releasing IUD group and in the ablation group put greater emphasis on a minimally invasive intervention with or without a short hospital stay. In women undergoing ablation, 70% of the patients preferred this treatment and the levonorgestrel-releasing IUD to hysterectomy in cases in which the success rate of noninvasive treatment was presumed to be 50%. In women having a levonorgestrel-releasing IUD inserted, 95% of the patients preferred this approach over hysterectomy in cases in which the success rate of this device was presumed to be 50%, whereas 35% of patients preferred ablation over hysterectomy in cases in which the success rate of ablation was presumed to be 50%. In women undergoing hysterectomy, 30% would have opted for ablation and 45% would have opted for a levonorgestrel-releasing IUD in cases in which success rates were 50%. Of patients who opted for hysterectomy, however, 60% stated that they would have preferred a noninvasive treatment if the success rate of this type of treatment were >80%. CONCLUSION(S): A majority of the patients who had dysfunctional uterine bleeding and who were scheduled for an endometrial ablation or a levonorgestrel-releasing IUD were inclined to take a risk of 50% likelihood of treatment failure to avoid a hysterectomy. As a consequence, research of treatment for dysfunctional uterine bleeding should focus on this 50% success level.

Adult↗
PubMed2000

Contraceptive effects of levonorgestrel implants in a marsupial.

The effect of subcutaneous levonorgestrel implants on reproduction in female tammar wallabies was investigated during the breeding and non-breeding season. Female tammars were given either a control or a levonorgestrel implant and their pouch young were removed to terminate embryonic diapause. Both the control and the levonorgestrel-implant animals treated during the months of May and June gave birth, demonstrating that levonorgestrel does not prevent the reactivation of the diapausing blastocyst or its subsequent development when given at these times. However, none of the levonorgestrel-treated animals mated post partum, whereas all of the control females that gave birth had a post partum oestrus and mated. Control animals gave birth again when the neonate was removed, and continued to breed normally during the following 36 months of the investigation. None of the levonorgestrel-treated animals gave birth again or mated during the next 36 months. Animals given control implants during December did not reactivate or give birth until the normal start of the breeding season in late January. Animals treated with levonorgestrel implants during December did not reactivate with the control animals at the beginning of the breeding season and did not give birth during the next 36 months. There were no effects of levonorgestrel treatment on early lactation. Levonorgestrel implants were removed from six females and four of these animals resumed reproductive activity, confirming that the contraceptive effect of the implants is reversible. Levonorgestrel implants therefore provide a highly effective, reversible and long-term method of contraception for tammar wallabies. This contraceptive system appears to offer a method of population control for the management of overabundant captive and selected wild populations of macropodid marsupials.

Animals↗
PubMed2004

Benefit-risk assessment of the levonorgestrel intrauterine system in contraception.

The levonorgestrel-releasing intrauterine system (IUS) is a long-acting, fully reversible method of contraception. It is one of the most effective forms of contraception available, and combines the advantages of both hormonal and intrauterine contraception. The levonorgestrel-releasing IUS also gives the users many non-contraceptive benefits: the amount of menstrual bleeding and the number of days of menstrual bleeding are reduced, which makes it suitable for the treatment of menorrhagia (heavy menstrual blood loss). Dysmenorrhoea (painful menstruation) and premenstrual symptoms are also relieved. In addition, the levonorgestrel-releasing IUS provides protection for the endometrium during hormone replacement therapy. The local release of levonorgestrel into the uterine cavity results in a strong uniform suppression of the endometrial epithelium as the epithelium becomes insensitive to estradiol released from the ovaries. This accounts for the reduction in menstrual blood loss. All possible patterns of bleeding are seen among users of the levonorgestrel-releasing IUS; however, most of the women who experience total amenorrhoea continue to ovulate. The first months of use are often characterised by irregular, scanty bleeding, which in most cases resolves spontaneously. The menstrual pattern and fertility return to normal soon after the levonorgestrel-releasing IUS is removed. The contraceptive efficacy is high with 5-year failure rates of 0.5-1.1 per 100 users. The absolute number of ectopic pregnancies is low, as is the rate per 1000 users. The levonorgestrel-releasing IUS is equally effective in all age groups and the bodyweight of the user is not associated with failure of the method. In Western cultures continuance rates among users of the levonorgestrel-releasing IUS are comparable with those of other long-term methods of contraception. Premature removal of the device is most often associated with heavy menstrual bleeding and pain, as with other long-term methods of contraception, and is most common in the youngest age group. When adequately counselled about the benign nature of oligo- or amenorrhoea, most women are very willing to accept life without menstruation. The risk of premature removal can be markedly diminished with good pre-insertion counselling, which also markedly increases user satisfaction. User satisfaction is strongly associated with the information given at the time of the levonorgestrel-releasing IUS insertion. Thus, the benefits of the levonorgestrel-releasing IUS make it a very suitable method of contraception for most women.

Administration, Intravaginal↗
PubMed1998

Levonorgestrel subdermal implants. A review of contraceptive efficacy and acceptability.

UNLABELLED: Levonorgestrel 6-capsule subdermal implants (Norplant) are an effective form of reversible contraception. When implanted under the skin of the upper arm, they release drug into the circulation at a relatively constant rate over 5 years. Generally, the cumulative pregnancy rate at the end of 5 years' levonorgestrel implant use is less than 2 per 100 users. The implants provide contraceptive efficacy equivalent to, or better than, that provided by other reversible methods (including oral contraceptives). Younger women are more likely than older women to become pregnant while using levonorgestrel implants. Bodyweight was positively correlated with risk of pregnancy in a number of studies, but may not be a factor with the currently available 6-capsule implant formulation. Limited data suggest that a new 2-rod levonorgestrel subdermal system (Jadelle) is as effective as the more extensively studied 6-capsule system and has a similar tolerability profile. Fertility returns rapidly after the implants are removed. Use of levonorgestrel subdermal implants is compatible with breast-feeding. In several studies, discontinuation rates were 2 to 15% during the first year of use; cumulative 5-year discontinuation rates ranged from 22 to 64 per 100 women. Despite a substantial incidence of adverse events during therapy, levels of user satisfaction are generally high. Menstrual abnormalities (increased or decreased menstrual flow, spotting, irregularity and amenorrhoea) affect most women at some time during therapy and are the most frequent reason for discontinuing levonorgestrel implants before the end of 5 years' treatment (incidence of 4.2 to 30.7 per 100 users). Mood changes and headache also may lead to discontinuation. Other reported adverse events include skin reactions (including acne), dizziness and weight gain. Serious adverse events (such as stroke, thrombotic thrombocytopenia and idiopathic intracranial hypertension) have been reported during levonorgestrel implants therapy, but the population incidence is difficult to calculate and causality is unclear. According to 3 pharmacoeconomic analyses from an institutional or managedcare perspective, all contraceptive interventions result in net cost savings. It is not clear whether levonorgestrel implants provide greater or smaller economic benefits than combined oral contraceptives. CONCLUSION: Levonorgestrel subdermal implants provide effective long term contraception. Despite a high incidence of menstrual adverse events, overall levels of user satisfaction are high, and 1-year continuation rates are better than those for combined oral contraceptives. Levonorgestrel subdermal implants are a good choice of contraceptive method in women who desire effective contraception, but who are unable to, or prefer not to, comply with an oral regimen.

Contraceptive Agents, Female↗