Pharmacokinetic and pharmacodynamic studies of levonorgestrel-releasing intrauterine device

Intrauterine devices releasing 20 micrograms/day levonorgestrel were inserted in 10 women (ages 25-34). Bleeding and spotting patterns were recorded on a menstrual card during one year of follow-up. Blood samples were collected for radioimmunoassays of LH, estradiol (E2), progesterone (P) and levonorgestrel (LNG) and for sex hormone binding globulin (SHBG) 3 times a week during the 1st month of use, and twice a week during the 6th and 12th treatment months. Among the 10 women, two experienced irregular cycles with prolonged intermenstrual spotting, four had amenorrhea in the latter part of treatment months, while the other four had regular cycles. According to the serum levels of E2 and P, the hormone profiles were divided into four types of reaction: A) anovulatory, B) anovulatory but with high follicular activity, C) ovulatory but with luteal insufficiency, and D) ovulatory. Among the 29 treatment cycles, there were 10 D-type, 3 C-type, 13 B-type and 3 A-type of ovarian reactions: 44.8% of the cycles were ovulatory (C + D) and 55.2% were anovulatory (A + B). In general, serum levels of levonorgestrel were low in ovulatory cycles and were high in anovulatory cycles. The difference was statistically significant. There were marked individual differences. The decline of serum LNG from the 1st (492 pmol/l) to the 6th (320 pmol/l) treatment months was 34.9% on average. The amenorrheic cycles coincided mostly with the hormonal profile of ovulatory types, which indicated that the cause of amenorrhea is due to the local effect of levonorgestrel on the endometrium. The levonorgestrel levels were significantly correlated with serum SHBG, r = 0.8856, p less than 0.001, and with E2, r = 0.4661, p less than 0.05.     

The effect of a levonorgestrel-releasing intrauterine device in the treatment of myoma-related menorrhagia

In this open observational study we evaluated the effectiveness of a levonorgestrel-releasing intrauterine device (LNG-IUD) in the treatment of myoma-related menorrhagia. Nineteen patients with recurrent menorrhagia lasting more than 3 months and with fibromyomatosus uterus were treated for 12 months with a LNG-IUD releasing 20 micro g/day of levonorgestrel. Menstrual blood loss, measured objectively by the pictorial blood loss assessment chart score (PBAC), level of serum hemoglobin and pattern of uterine bleeding were recorded at 3, 6, 9 and 12-month follow-up visits. Median monthly PBAC score during the two menstrual cycles before treatment was 310. After LNG-IUD, the PBAC score gradually decreased from a median value of 186 at 3 months to a median value of 155, 108 and 96 at 6, 9 and 12 months of treatment, respectively. Despite the statistically significant reduction of PBAC score, persistent menorrhagia, defined as a monthly PBAC score of 100 or higher, was observed at 12 months in 14 patients, whereas only one woman was amenorrheic and 4 were hypomenorrheic. In conclusion our study demonstrates the clinical reduced effectiveness of LNG-IUD in the treatment of myoma-related menorrhagia.     

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

A copper-releasing IUD and levonorgestrel-releasing IUDs releasing 30 μg and 10 μg 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-μg per day levonorgestrel-releasing IUD group, initially high plasma levonorgestrel concentrations reached a plateau four weeks after the insertion. In the 10-μg per day levonorgestrel-releasing IUD group, the plasma concentrations of levonorgestrel stabilized after the initial two weeks.     

Patterns of ovulation and bleeding with a low levonorgestrel-releasing intrauterine device

Patterns of bleeding and plasma concentrations of levonorgestrel, progesterone, estradiol, LH and FSH were studied in ten volunteers who had a levonorgestrel-releasing IUD inserted postmenstrually. The IUD was designed to release 12 microgram/day. All but two of the volunteers ovulated during treatment. The ovulatory cycles differed from the control cycles by being longer and by having depressed plasma progesterone levels during the luteal phases. Intermenstrual spottings occurred frequently during the first sixty days of treatment. No pregnancies occurred during the course of the study.     

Five years' experience with a small intracervical/intrauterine levonorgestrel-releasing device

OBJECTIVE: A randomized study was performed to compare the efficacy, safety and acceptability of a new model of an intracervical/intrauterine contraceptive device (ICD) releasing 20 microg of levonorgestrel (LNG) per day. METHODS: The LNG-ICD was inserted in Group I into the cervical canal and in Group II into the uterine cavity. Group I included 151 women (age, 18-43 years) whereas Group II included 147 (age, 19-43 years). The number of nulliparous women was 145. RESULTS: The 5-year results are presented here. The results showed a total continuation rate of 50%; the continuation rate in the cervical group and that in the uterine group were 53.6% and 46.3%, respectively--the difference being statistically insignificant (p=.3593). The main reason for termination was a wish for pregnancy, which is explained by the relatively young age and degree of nulliparity of the study population. During the first year, two pregnancies occurred in both groups. Two of these were ectopic, one in each group. The other two occurred after unnoticed expulsions. Thereafter, no pregnancies occurred. The cumulative gross rate for pregnancy was 1.3 and the Pearl index at 5 years was 0.425. The total expulsion rate was relatively high (11.1%). Expulsions occurring during the first few months of the first year were related to insertion. Removals because of bleeding and because of amenorrhea were low, the combined gross rate being 5.7 and the Pearl rate 1.8 at 5 years. Also, the gross rate of infection was low (0.7). The continuation was high in spite of a high rate of removals for planning pregnancy (15.4). CONCLUSIONS: The method is safe and effective. There were only minor differences between the groups. There were no perforations and the incidence of infection was low. The device can also be used by young nulliparous women.     

Vaginal flora changes on Pap smears after insertion of levonorgestrel-releasing intrauterine device

Background

The levonorgestrel intrauterine system (LNG-IUS) combines a uterine foreign body and the continuous release of low-dose levonorgestrel for contraception. Its influence on the rate of vulvovaginal infections and flora disturbance is insufficiently known, but important for contraceptive advice in women, especially those who develop recurrent vaginosis or Candida vulvovaginitis.

Study Design

Slides of 286 women who had a Pap smear taken before and 1 to 2 years after placement of a LNG-IUS were blindly reviewed for the presence of abnormal vaginal flora (AVF), bacterial vaginosis (BV), aerobic vaginitis (AV) and Candida vaginitis (CV).

Results

Prior to insertion, there were no differences in vaginal flora abnormalities between women using different kinds of contraception. LNG-IUS users did not have different rates of AVF, BV, AV or CV, but the general risk to develop any infection was increased. Uterine bleeding after insertion did not seem to predict a different flora type.

Conclusion

We found that Pap smears suggested more vaginal infections after 1 year of LNG-IUS use than prior to insertion of the device.     

Return to fertility after removal of a levonorgestrel-releasing intrauterine device and Nova-T

In a European randomized multicenter study, the efficacy and safety of an intrauterine contraceptive device releasing 20 microgram levonorgestrel/24 hours (LNG-IUD) have been evaluated and compared to the Nova-T. Because the LNG-IUD has a strongly suppressive effect on the endometrium and in some women affects ovarian function, the return to fertility after removal of the IUD was studied. Two-hundred-nine women (71 in the Nova-T and 138 in the LNG-IUD group), who had their IUDs removed because of planning pregnancy, were followed at least 24 months or until termination of pregnancy. For the Nova-T, the cumulative conception gross rate was 71.2/100 women after 12 months (79.7 after 24 months) and for the LNG-IUD 79.1 (86.6 after 24 months). The difference between the devices is not statistically significant, and in spite of the endometrial suppression during use of LNG-IUD, there is no delay of return to fertility and in both groups 96% of the pregnancies occurred during the first year after removal of the device. Eighty-four % of the pregnancies in the Nova-T group and eighty-six % in the LNG-IUD group ended in live births. The results suggest that the endometrium recovers quickly, normal ovulations are established and the fertility seems to be unaffected after use of an LNG-IUD.     

Clinical performance of a new levonorgestrel-releasing intrauterine device. A randomized comparison with a nova-T-copper device

The clinical performance of two levonorgestrel-releasing intrauterine devices (IUDs) with different release rates was studied and compared with a copper-releasing Nova-T device in a randomized partly double-blind multiclinical trial. Special attention was given to patterns of bleeding, hormonal side-effects, blood pressure and body weight. The clinical acceptability of the levonorgestrel IUDs was as good as that of the copper-releasing IUD. A highly significant decrease in the amount of menstrual blood loss was seen with the levonorgestrel-IUDs, the users of which experienced fewer days of bleeding than prior to insertion. Patients suffering from dysmenorrhea experienced relief from this symptom after insertion of a levonorgestrel-IUD. Some side-effects, usually referred to as hormonal, increased during the levonorgestrel-IUD use, but did not result in higher termination rates than with the Nova-T device. No changes in body weight were recorded for the levonorgestrel-IUDs and a slight decrease in both systolic and diastolic blood pressure was found after one year of use. No infections were recorded.     

Management of the malpositioned levonorgestrel-releasing intrauterine system

BackgroundThe management of a malpositioned levonorgestrel (LNG)-releasing intrauterine system (IUS) can present a clinical challenge, complicated by the high cost of replacing it with a new device. We tried to challenge the guidelines and common practice that usually suggest prompt removal of any malpositioned IUS and replacement with a new one.Study DesignWe present our experience with 18 patients in whom the LNG-releasing IUS was found during a routine sonographic evaluation to be displaced towards the cervical canal 2 to 36 months postinsertion. Using an alligator forceps, the device was repositioned in the uterine cavity.ResultsThe procedure was deemed successful in 17 (94.4%) of 18 cases. In 3 (17.6%) of the 17 successful procedures, the LNG-releasing IUS was found again to be malpositioned within 2 months. No complications were noted, and no postprocedural infection occurred.ConclusionRepositioning of a malpositioned LNG-releasing IUS should be considered, as it is an easy and simple manipulation that can be done in the office with a high success rate and minimal risk of complications.     

Effect of levonorgestrel-releasing intrauterine device on hormonal profile and menstrual pattern after long-term use

In the present study 14 women after 6 years' use of levonorgestrel-releasing IUD were investigated for the changes of LH, progesterone (P), estradiol (E₂), prolactin (PRL) and serum binding globulin (SHBG) in relation to the levonorgestrel levels throughout a segment of 26–40 days with the aim of comparing the hormonal profiles with those during the first year of use of Lng-IUD. Ultrasound scanning was used to follow the development of follicles along with the RIA measurement of hormones. The results of serum LH, P and E₂ showed ovulation in 11 cases with either normal menstrual cycles (5 cases), prolonged or irregular cycles (4 cases) or with amenorrhea for 2–3 years (2 cases). One case showed insufficiency of luteal function and 2 cases showed anovulation but with follicular hyperactivity. Higher percentages of ovulatory cycles (78.5%) were found after 6 years of use. No case of complete suppression of ovulation was found. Anovulatory cycles only constituted 14.3%. Clinically, the development of follicles followed by ultrasound scanning further confirmed the hormonal findings. The persistent enlargement of follicles coincided with high levels of E₂. After 6 years of use, the serum levels of levonorgestrel were still maintained at mean levels of 314.26 pmol/L and 470.63 pmol/L in the ovulatory and anovulatory groups, respectively. It is concluded that over two-thirds of the cases have ovulatory cycles after long-term use of Lng-IUD; the contraceptive effect is mainly due to its local action on the endometrium, with much less effect on the ovarian function.     

左炔诺孕酮宫内缓释系统与Tcu380A临床效果比较

目的:比较放置左炔诺孕酮宫内缓释系统与Tcu380A的临床效果。方法:择门诊要求放置IUD的健康经产妇女267例,分别放置左炔诺孕酮宫内缓释系统102例(Ⅰ组)和Tcu380A166例(Ⅱ组),随访24个月,对其不良反应、避孕效果、因症取出和续用率进行观察对比。结果:使用左炔诺孕酮宫内缓释系统妇女的带器妊娠率、疼痛发生率、月经经期、经量、因症取出率低于使用Tcu380A的妇女(P<0.05),脱落率两者比较差异无统计学意义(P>0.05)。两组续用率分别为92.4%和87.3%,左炔诺孕酮宫内缓释系统高于Tcu380A,差异有统计学意义(P<0.05)。结论:左炔诺孕酮宫内缓释系统避孕效果好、副作用少,值得广泛推荐使用。     

The effect of levonorgestrel-releasing intrauterine device on menorrhagia in women taking anticoagulant medication after cardiac valve replacement

Background

This study was conducted to evaluate the effect of levonorgestrel-releasing intrauterine devices (LNG-IUDs) on menorrhagia in patients receiving anticoagulant therapy after cardiac valve replacement.

Study Design

Forty women with menorrhagia who underwent cardiac valve replacement and were taking anticoagulant medication were enrolled in the study. The women were randomly divided into two groups: LNG-IUDs were inserted into 20 women in Group 1 over the first 3 days of menstrual bleeding, while the women in Group 2 were followed without any intervention. The activated partial thromboplastin time, prothrombin time, international normalized ratio, hematocrit level, hemoglobin level, ferritin level and pictorial bleeding assessments for the quantity of menstrual bleeding were recorded.

Results

Three months after insertion of LNG-IUDs, the women in Group 1 had a significant decrease in blood loss and higher hemoglobin, hematocrit and ferritin values. No difference was detected for these parameters in the control group at the third and sixth months of the study. Coagulation parameters did not differ between the two groups.

Conclusion

LNG-IUDs can be considered as an effective non-surgical treatment for menorrhagia in women receiving anticoagulant therapy after cardiac valve replacement.     

Effective contraception with the levonorgestrel-releasing intrauterine device: 12-month report of a European multicenter study

The use-effectiveness of an intrauterine contraceptive device releasing 20 mcg of levonorgestrel daily (Lng-IUD), and of a Nova T copper-releasing IUD, were studied in a randomized, comparative multicenter trial. The Lng-IUD was inserted in 1821, and the Nova T in 937 women. The 12-month net pregnancy rate with the Lng-IUD (0.1 per hundred women) was significantly lower than that with the Nova T (0.9 per hundred). Removal rates for menstrual problems and/or pain were similar for the two methods (net rates 7.5 and 8.7, respectively). The 12-month continuation rates were 82.2 for the Nova T and 79.7 for the Lng-IUD. The reduction of the bleeding led to oligomenorrhea and amenorrhea in users of the Lng-IUD; the removal rate for these reasons was 1.4. The removal rate for hormonal side effects with the Lng-IUD was 2.4. Blood hemoglobin concentrations increased among users of the Lng-IUD and decreased among users of the Nova T. The results show that the Lng-IUD was a highly effective contraceptive method which reduced menstrual bleeding. It is a promising alternative for women desiring a highly effective method for long-term use.     

Duration of breast-feeding and development of children after insertion of a levonorgestrel-releasing intrauterine contraceptive device

IUDs releasing levonorgestrel, 10 μg per day (30 patients) and 30 μg per day (40 patients), and copper-releasing IUDs (Nova-T) (40 patients) were inserted six weeks after delivery in 110 breast-feeding amenorrheic women. The infants were carefully followed-up by recording monthly weight gain and growth, age of eruption of the first tooth, age of being able to walk without support and morbidity to infective diseases. No differences were noticed between the study groups. Plasma samples were collected from 13 children at the age of eight months, while the mothers were breast-feeding. Six mothers had a levonorgestrel-releasing IUD and seven others the Nova-T or no hormonal or intrauterine contraceptive. No differences were noticed between the groups in Na, K, Cl, Ca, P, protein, albumin, creatinine, urate, Fe, cholesterol, triglyceride, bilirubin, alkaline phosphatase, aspargine aminotransferase, alanine aminotransferase, lactate-dehydrogenase or high density lipoprotein cholesterol serum concentrations in the children. The duration of breast-feeding and initiation of supplementary feeding was recorded. The continuation of breast-feeding 75 days after the insertion of a 30-μg per day levonorgestrel-releasing IUD was 56 percent while in the Nova-T group only 21 percent had discontinued which is a statistically significant difference (p < 0.05); later the difference disappeared. Compared with the lactation time of their previous breast-feeding reported by women in both groups, the present lactation time increased by ten weeks. The infants received substitute foods including substitute milk, juices, etc., in the Nova-T group at 3.9 months and in the levonorgestrel-releasing IUD group at 3.4 months after delivery.     

左炔诺孕酮宫内缓释系统治疗子宫腺肌病痛经的临床观察

目的 探讨左炔诺孕酮宫内缓释系统(LNG-IUS)用于治疗子宫腺肌病痛经的机制,并观察其不良反应及对内分泌的影响.方法 2004年7月至2006年7月,选择患子宫腺肌病的已孕患者48例,于月经周期第5～8天放置LNG-IUS.分别在放置前,放置后3、12个月观察患者痛经情况、月经量、血红蛋白、子宫体积及血清卵泡刺激素(FSH)、黄体生成素(LH)、雌激素(E2)水平的变化.结果 放置LNG-IUS后12个月患者痛经评分明显降低(P＜0.01);月经量明显减少[(21.3±11.6)ml比(224.5±67.5)ml](P＜0.01);血红蛋白较放置前明显增加[(135.0±21.0)g/L比(107.0±13.0)g/L](P＜0.05);子宫体积较放置前明显减小[(401.4±158.4)cm3比(665.6±245.3)cm3](P＜0.01);血清FSH、LH、E2水平较放置前无明显变化(P＞0.05).结论 放置LNG-IUS后能有效减轻患者的临床症状,提高患者的生活质量,对卵巢功能无影响,有很好的临床应用价值.     

左炔诺孕酮宫内缓释系统治疗子宫腺肌病的疗效观察

目的:探讨左炔诺孕酮宫内缓释系统(LNG-IUS)治疗子宫腺肌病的临床价值。方法:观察100例子宫腺肌病患者放置LNG-IUS前后痛经、月经量、子宫体积、子宫内膜厚度、血清CA125、血红蛋白及激素水平的变化。结果:放置LNG-IUS3、6、12个月后痛经明显缓解;月经量明显减少;子宫内膜变薄;血清CA125下降;贫血得以纠正(P<0.01)。血清FSH、LH、E2水平及子宫体积无变化。结论:LNG-IUS治疗子宫腺肌病能有效地提高患者的生活质量,对卵巢功能无明显影响,为一种较好的保守治疗手段,有临床应用价值。