Levonorgestrel intrauterine system (LNG-IUS) with conjugated oral equine estrogen: a successful regimen for HRT in perimenopausal women.

BACKGROUND: This study was designed to assess the long-term efficacy (5 years) of the levonorgestrel-releasing intrauterine system (LNG-IUS) in protecting the endometrium from hyperplasia during estrogen replacement therapy in perimenopausal women. METHODS: Prospective, open, outpatient clinical trial in London and Oxford. Eighty-two women received oral conjugated equine estrogen 1.25 mg daily and LNG-IUS releasing 20 mug levonorgestrel per 24 h. Endometrial biopsy and histological assessment were performed annually. Endometrial thickness was measured by vaginal ultrasonography. RESULTS: Non-proliferative endometrium was present at the end of cycles 12, 24, 36, 48 and 60 in 98.6, 98.6, 95.5, 96.8 and 95.2% of the participants respectively. No endometrial hyperplasias were confirmed throughout a period of 60 cycles. The proportion of amenorrhoeic women increased from 54.4% at 12 cycles to 92.7% at the end of the study. The continuation rate per 100 women at 60 cycles was 79.84 (95% CI 71.0-88.6). CONCLUSIONS: The LNG-IUS with estrogen supplementation in perimenopausal women suppresses endometrial proliferation resulting in amenorrhoea and relieves vasomotor symptoms. The treatment regimen is well tolerated and provides an alternative strategy for perimenopausal women with the likelihood of increasing compliance.

Five-year clinical experiences with NOVA T 380 copper IUD.

In an open, single-group, phase III clinical trial of 5 years, the clinical performance of NOVA T 380 was investigated in three centers. The device having a higher copper surface of 380 mm(2) is a modification of NOVA T. A total of 400 voluntary women were enrolled in the study. The mean age was 31.4 years (SD 5.5) with the minimum of 18 and the maximum of 44 years. At the end of the study, 211 women had passed the 60-month visit. Cumulative discontinuation rates at the end of the first and the fifth year calculated by Kaplan-Meier estimates, were respectively as follows: pregnancy 0.5 and 1.9, expulsion 1.3 and 4.1, bleeding 4.4 and 14.0, pain 1.3 and 4.2, removal for other medical reason 1.4 and 6.4, planning pregnancy 0.8 and 13.5, and removal for other personal reason 2.4 and 11.9 per 100 users. Neither ectopic pregnancies nor episodes of pelvic inflammatory diseases (PIDs) occurred. One perforation was recorded; the calculated rate is 0.3 per 100 women (first year). The continuation rate was 88.3 and 52.5 at 1 and 5 years, respectively. In conclusion, the 5-year performance of NOVA T 380 was good compared to other "high-loaded" copper devices. Safety was acceptable over the entire study period.

A 5-year follow-up study on the use of a levonorgestrel intrauterine system in women receiving hormone replacement therapy.

OBJECTIVE: To investigate endometrial histology, bleeding, and the effects of replacing the levonorgestrel intrauterine system (LNG IUS, Mirena/Levonova, Leiras Oy, Turku, Finland) after 5 years of combined use with estrogen. DESIGN: Prospective cohort study. SETTING: Private outpatient clinic. PATIENT(S): Forty postmenopausal women started hormone replacement therapy with LNG IUS and either a patch (50 microg/24 h) or oral (2 mg) estradiol valerate protocol. Thirty-nine completed 12 months of treatment. Twenty-nine of them had used LNG IUS with continuous estradiol replacement therapy for 5 years. Seven of them volunteered to a 3-month treatment-free period before reinsertion; 22 opted for immediate reinsertion. INTERVENTION(S): Endometrial sampling for histology, endometrial thickness, and location of the LNG IUS by ultrasound at removal and after washout. The women completed bleeding diaries from 3 months prior to removal to 3 months after reinsertion. MAIN OUTCOME MEASURE(S): Endometrial histology was evaluated and estrogen and progestin effects were also investigated. Endometrial thickness was measured. Bleeding was examined based on bleeding diaries. The investigator and the women evaluated the insertion, removal, and reinsertion of the LNG IUS. RESULT(S): At 6 and 12 months endometrial histology was nonproliferative. At removal, all endometria were suppressed and a strong progestin effect was seen. The thickest endometrium was 3.6 mm. After washout, all seven endometria were atrophic. Before the IUS was replaced, 26 women were amenorrheic, whereas three had minor spotting. After replacement 5 women had no bleeding and an additional 10 women had only spotting. The bleeding or spotting discontinued within 18 days. The insertion of LNG IUS was characterized as easy by the investigator and it was well tolerated by the women. Cervical dilatation and/or paracervical blockade was used in 10 insertions. CONCLUSION(S): Intrauterine levonorgestrel effectively protects against endometrial hyperplasia. In most women it induces amenorrhea, which is only temporarily affected by replacement of the LNG IUS.

Sixty thousand woman-years of experience on the levonorgestrel intrauterine system: an epidemiological survey in Finland.

OBJECTIVE: An epidemiological survey was carried out in Finland to establish the performance of the levonorgestrel intrauterine system (LNG-IUS) in a large population of women regularly using the system for contraception. STUDY DESIGN: All women who had LNG-IUS inserted between 1990 and 1993 were sent a questionnaire with questions about general health status, reproductive and contraceptive history and gynecological problems and a set of questions about their experience on the LNG-IUS. RESULTS: The women who had a LNG-IUS inserted between April 1990 and December 1993 were asked to participate in an epidemiological survey. At the insertion visit, the women were asked to fill in a questionnaire, to consent to further use of the information by signing their initials and to return the questionnaire to the manufacturer. The number of returned forms was 23,885. The names and addresses of these women were acquired from the National Register and a questionnaire with 75 questions was sent to them. Of the questionnaires, 75% were returned. Experience covered 58,600 woman-years. The mean age of the users of the LNG-IUS was 40 years. Most of them (99.3%) were parous, most often with two or three children. The cumulative 5-year Pearl index was 0.18 and there were 108 pregnancies in the study population during the use of the LNG-IUS. The continuation rates for 1, 2, 3, 4 and 5 years were 0.94, 0.87, 0.82, 0.76 and 0.65, respectively. Removal before the full 5 years was most common among the youngest age group. Bleeding disorders, infections and pain during LNG-IUS use were associated with the highest risk for discontinuation. The risk of premature removal was markedly diminished among women with totally or occasionally missed periods. CONCLUSIONS: The response rate to the survey was high and the sample studied was exceptionally large. The continuation rate of LNG-IUS was high up to 5 years. The symptoms associated with premature removal agreed with results from earlier randomized studies of the LNG-IUS.

Sixty thousand woman-years of experience on the levonorgestrel intrauterine system: an epidemiological survey in Finland.

OBJECTIVE: An epidemiological survey was carried out in Finland to establish the performance of the levonorgestrel intrauterine system (LNG-IUS) in a large population of women regularly using the system for contraception. STUDY DESIGN: All women who had LNG-IUS inserted between 1990 and 1993 were sent a questionnaire with questions about general health status, reproductive and contraceptive history and gynecological problems and a set of questions about their experience on the LNG-IUS. RESULTS: The women who had a LNG-IUS inserted between April 1990 and December 1993 were asked to participate in an epidemiological survey. At the insertion visit, the women were asked to fill in a questionnaire, to consent to further use of the information by signing their initials and to return the questionnaire to the manufacturer. The number of returned forms was 23,885. The names and addresses of these women were acquired from the National Register and a questionnaire with 75 questions was sent to them. Of the questionnaires, 75% were returned. Experience covered 58,600 woman-years. The mean age of the users of the LNG-IUS was 40 years. Most of them (99.3%) were parous, most often with two or three children. The cumulative 5-year Pearl index was 0.18 and there were 108 pregnancies in the study population during the use of the LNG-IUS. The continuation rates for 1, 2, 3, 4 and 5 years were 0.94, 0.87, 0.82, 0.76 and 0.65, respectively. Removal before the full 5 years was most common among the youngest age group. Bleeding disorders, infections and pain during LNG-IUS use were associated with the highest risk for discontinuation. The risk of premature removal was markedly diminished among women with totally or occasionally missed periods. CONCLUSIONS: The response rate to the survey was high and the sample studied was exceptionally large. The continuation rate of LNG-IUS was high up to 5 years. The symptoms associated with premature removal agreed with results from earlier randomized studies of the LNG-IUS.

The levonorgestrel intrauterine system in contraception.

The levonorgestrel intrauterine system (LNG IUS) releases 20 microg/24 h of levonorgestrel from a polymer cylinder mounted on a T-shaped frame and covered with a release rate-controlling membrane. It is approved for 5-year use. The most outstanding features of LNG IUS are its high contraceptive efficacy and reduction of menstrual blood flow. No single mode of action can account for its contraceptive efficacy. The endometrium becomes thin and inactive, and the cervical mucus turns scanty and viscous. Although ovulation may be disturbed to some degree, estradiol production continues normally. The Pearl index for LNG IUS from large clinical trials is 0.1. Extrauterine pregnancies occur in 1 in 5000 users per year. Both the volume of menstrual blood loss and the number of bleeding days are reduced. During the first year of use, 20% of women become amenorrheic. There is an initial increase in the mean number of bleeding and spotting days, but in 3 to 6 months the number of bleeding and spotting days is the same as observed in copper IUD-users. The variation between individuals is wide and unpredictable. There are also additional health benefits secondary to the inactivation of the endometrium: increased hemoglobin, decreased dysmenorrhea, a possible decrease in pelvic inflammatory disease. LNG IUS may also decrease the growth of fibroids. LNG IUS is well accepted by users, with typical annual continuation rates above 80% in clinical studies.

Length of use and symptoms associated with premature removal of the levonorgestrel intrauterine system: a nation-wide study of 17,360 users.

OBJECTIVE: To establish the continuation rates of the levonorgestrel intrauterine system (LNG IUS) and symptoms associated with its premature removal. SAMPLE AND SETTING: All women in Finland who had a LNG IUS inserted between April 1990 and December 1993 and whose doctor had filled in and returned a form at the insertion visit. This study population consists of 46% of all the LNG IUSs sold in Finland between 1990 and 1993. DESIGN: A questionnaire on reproductive and contraceptive history, gynaecological problems and symptoms experienced during the use of the LNG IUS was sent to 23,885 LNG IUS users. A total of 17,914 questionnaires were returned (response rate 75%). The results cover experience from 58,600 woman years. A log-rank-test was used to test differences in continuation rates. Multivariate analyse were performed using Cox's proportional hazard model. RESULTS: The LNG IUS was prematurely removed from 5175 women. The one, two, three, four and five year continuation rates were 93%, 87%, 81%, 75% and 65%, respectively. The symptoms during the use of the LNG IUS most strongly associated with its premature removal were excessive bleeding and spotting, and infections and pain. The risk of premature removal was markedly lower among women who had occasional or total absence of menstruation. Premature removal was less likely in the oldest age group. CONCLUSIONS: The continuation rate of the LNG IUS compares favourably with other long-acting contraceptive systems. Totally or occasionally absent menstruation was strongly associated with prolonged continuation.

Two-year clinical experience with Nova-T 380, a novel copper-silver IUD.

In 1992, an open single-group phase III clinical trial was started at three centers to investigate the clinical performance of the high copper surface area Nova-T 380, a modification of Nova-T. This report presents the interim results of the first two years of use. A total of 400 women volunteers were enrolled in the study. The mean age was 31.4 years (SD 5.5) with a minimum of 18 and a maximum of 44 years. At the cut-off date, 259 women had passed the 24-month visit. Gross cumulative life-table rates at the end of the first and second years, respectively, calculated by the Kaplan-Meier method, were as follows: pregnancy 0.5 and 1.6, expulsion 1.6 and 2.8, bleeding 4.7 and 8.7, pain 1.3 and 2.3, removal for other medical reasons 1.7 and 3.9, planning pregnancy 1.1 and 6.0, removal for other personal reasons 0.5 and 1.5, per 100 users. No ectopic pregnancies or PIDs occurred. The continuation rates were 89.0 and 75.5 at 12 and 24 months, respectively. The first two-year performance of the Nova-T 380 was good. Bleeding problems were in the same range as with devices with smaller copper surface areas. No unexpected serious adverse events were encountered.

Prostacyclin and thromboxane in pregnant and nonpregnant women in response to exercise.

OBJECTIVES: To compare the effects of a 30-minute standardized submaximal exercise test on the urinary excretion of the metabolites of prostacyclin and thromboxane A2 in healthy pregnant and nonpregnant women. METHODS: Time-fixed urine samples were collected before, during, and after the exercise test from nine pregnant and six nonpregnant women, and the samples were assayed for 6-keto-prostaglandin (PG) F1 alpha and 2,3-dinor-6-keto-PGF1 alpha (prostacyclin metabolites), as well as for thromboxane B2 and 2,3-dinor-thromboxane B2 (thromboxane A2 metabolites) by high-pressure liquid chromatography and radioimmunoassay. RESULTS: Pregnancy itself was associated with a 3.6-4.3-fold rise in prostacyclin excretion, but with no significant change in thromboxane output. The exercise caused stimulation in both prostacyclin and thromboxane excretion. In response to exercise, the maximal rise in 6-keto-PGF1 alpha output was significantly larger among the pregnant subjects, but when compared with its pre-exercise excretion on a relative percentage scale, the range of rise in 6-keto-PGF1 alpha output (58-73%) was comparable in pregnant and nonpregnant subjects. Furthermore, excretion of 2,3-dinor-6-keto-PGF1 alpha rose similarly in the two study groups (68-166%) in response to exercise. The exercise caused a 2.3-fold rise in the output of thromboxane B2 excretion in both pregnant and nonpregnant women, but it stimulated (by a twofold rise) the excretion of 2,3-dinor-thromboxane B2 only in pregnant women. CONCLUSION: Physical activity may stimulate vasoactive prostacyclin and thromboxane excretion during pregnancy. Such changes may play a role in the regulation of blood flow during exercise.

Effect of exercise on placental blood flow in pregnancies complicated by hypertension, diabetes or intrahepatic cholestasis.

The effects of a standardized exercise test on intervillous placental blood flow were studied in 13 hypertensive, 10 diabetic and 8 cholestatic pregnant women in late pregnancy, and the results were compared with those of a normal control group. Analysis of variance for repeated measures revealed that in all the pathologic groups, placental blood flow was lower than in the controls. In all groups placental blood flow rose slightly 1 min after the cessation of exercise. The diabetics showed a decreased placental blood flow 30 min after the cessation of the exercise test (p less than 0.02). In diabetics, a fall was found in stroke volume, from 63 +/- 12 ml (mean +/- SD) before the exercise to 53 +/- 11 ml 30 min after the cessation of exercise (p less than 0.05), and a rise in peripheral vascular resistance, from 1540 +/- 200 (mean +/- SD) dynes/cm5 before exercise to 1750 +/- 390 dynes/cm5 30 min after the cessation of exercise (p less than 0.05). Pre-eclamptic patients had a higher peripheral vascular resistance than had normal controls. Pre-eclamptic, diabetic and cholestatic patients had lower cardiac index values than the normal subjects. The difference was significant in the pre-eclamptic and diabetic patients at 30 min after the cessation of exercise. Maternal heart rate, and systolic, diastolic and mean arterial blood pressures rose significantly from values at rest to values at the end of exercise in all groups. One of the pre-eclamptic patients showed a 74% decline in placental blood flow 1 min after the cessation of exercise coincident with fetal bradycardia.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of exercise on maternal hemodynamics and placental blood flow in healthy women.

Intervillous placental blood flow responses to standardized exercise during late pregnancy were studied using a Xenon technique in 25 healthy women. Thirteen of them were studied twice between the 32nd and 38th weeks of pregnancy, with mean 32 (range 22 to 40) days between the studies. At the end of a 6-min exercise, mean maternal heart rate had risen from 77 +/- 10 (SD) to 154 +/- 11 beats/min, amounting to 63% of maximal oxygen uptake. Stroke volume rose by 9%, cardiac output by 65% and cardiac index by 71% as a consequence of exercise, but peripheral vascular resistance declined by 41%. The placental blood flow was at a similar level after the exercise as before the exercise, being 95 +/- 19 (mean +/- SD) ml/min/100 ml of intervillous space before, 98 +/- 24 one min after, and 93 +/- 16 30 min after the cessation of exercise. No change was found in the level of placental blood flow between the 32-34th and 37-38th weeks of pregnancy. The placental blood flow had a positive correlation with maternal weight, mean arterial blood pressure and with diastolic blood pressure. Maternal heart rate, cardiac output, cardiac index, placental weight and the birth weight of the infant was not correlated with placental blood flow. It is concluded that in normal pregnancy a short submaximal exercise has little effect on placental blood flow measured after exercise.

Effect of short-term physical exercise on foetal heart rate and uterine activity in normal and abnormal pregnancies.

The response of a short-term submaximal bicycle ergometer test on foetal heart rate (FHR) and on uterine activity was studied in 61 pregnant women between pregnancy weeks 32 and 40. 28 of the women had uncomplicated pregnancies, 13 were hypertensive, 11 were diabetic, and 9 had intrahepatic cholestasis of pregnancy. After exercise, FHR declined in healthy subjects in pregnancy weeks past 35, whereas no significant change was found in such subjects before week 35 of pregnancy. Analysis of variance revealed a difference of FHR between subjects with umcomplicated and pre-eclamptic pregnancies in relation to time (p = 0.021). Exercise induced uterine contractions in hypertensive subjects. Foetal bradycardia was found in 2 healthy, in 2 pre-eclamptic, and in one cholestatic subject. In healthy pregnant women a non-reactive FHR with concomitant reduced FHR variability was found after exercise (P less than 0.01). The FHR variability of patients with pathologic pregnancies was less affected. These results suggest that, after a relatively strenuous short-term exercise, foetuses of mothers with uneventful pregnancies can be at risk of hypoxia in late pregnancy, but the clinical significance remains uncertain.

Pancreatic secretory trypsin inhibitor from human amniotic fluid and fetal and neonatal urine: concentrations and physicochemical characterization.

The levels and physicochemical properties of the pancreatic secretory trypsin inhibitor, also known as Kazal type trypsin inhibitor, were studied in human amniotic fluid. In the second trimester, the median concentration was 160 ng/ml, which exceeds the maternal serum levels 20-fold. Towards term, the amniotic fluid levels declined about 5-fold, whereas the maternal serum values remained constant. In fetal urine, the concentration of the trypsin inhibitor was similar to that in amniotic fluid in early gestation, whereas in newborn urine, the median level was 4-to 5-fold higher than in term amniotic fluid. The physiochemical characteristics of the trypsin inhibitor in amniotic fluid, neonatal urine and cancer urine from an ovarian cancer patient were similar, as studied by gel filtration, high performance reverse phase liquid chromatography, and complete immunological identity in immunodiffusion. The physicochemical similarity and levels in various compartments suggest fetal contribution to amniotic fluid levels of the trypsin inhibitor.

Release of beta-endorphin in response to physical exercise in non-pregnant and pregnant women.

The effect of physical exercise on beta-endorphin (beta-E) concentration in plasma was studied in 8 non-pregnant and in 8 pregnant women in their last trimester of pregnancy, using a 10-min bicycle ergometer test. In the non-pregnant women the mean beta-E levels were 2.4 +/- 0.7 (S.E.) pmol/l before the test, 4.3 +/- 0.9 pmol/l at the end of the test, and 4.3 +/- 0.6 and 5.0 +/- 2.0 pmol/l 15 and 30 min after the test, respectively, declining thereafter. In the pregnant women the mean beta-E values were 5.1 +/- 2.0 pmol/l before the test, 7.3 +/- 1.7 pmol/l at the end of the test, 6.7 +/- 2.0 pmol/l 15 min after the test, and 12.6 +/- 4.1 pmol/l 60 min after the test, declining thereafter. Thus, beta-E secretion increased in response to exercise both in non-pregnant and in pregnant women, the response lasting longer in pregnant women.

Effects of smoking on fetal heart rate variability during gestational weeks 27 to 32.

PIP: 8 healthy mothers in weeks 27-32 of pregnancy gave informed consent for this study of the effects of smoking on fetal heart rate. Analyses of fetal heart rate (FHR) variability were performed at 1-minute intervals from an abdominal fetal electrocardiogram 10 minutes before, during, and 25 minutes after the mother smoked. Maternal heart rate (MHR) was recorded manually. An elevation of MHR and blood pressure occurred during smoking. Blood pressure had returned to initial levels either immediately (systolic) or within 10 minutes (diastolic); however, MHR was still elevated 25 minutes after smoking ceased. Baseline FHR increased 5 minutes after maternal smoking and returned to the normal level in 25 minutes. Correlation analysis shows negative correlations between the differential index and FHR, between differential index and pulse pressure (p.001), between differential index and systolic reading (p.01), and between variability indexes and MHR (p.001). There was also a positive correlation between FHR and MHR as well as between interval and differential indexes (p.001). The main finding of this study is that, at the onset of the 3rd trimester, the human fetus shows the decreasing effects of smoking on both interval and differential indexes, as does the term fetus (the differential index describes the short-term variability and the interval index describes the long-term variability of heart rate).^ieng

Antepartum fetal heart rate variability and intervillous placental blood flow in association with smoking.

Intervillous placental blood flow and indices of fetal heart rate variability were measured from seven healthy pregnant women in the last trimester of pregnancy, once before and twice after smoking one cigarette. A blood flow reduction was observed in seven, a rise in five, and no change in two measurements. When intervillous placental blood flow decreased both indices of variability decreased (p less than 0.001), and when it increased the short-term component of fetal heart rate variability increased more significantly (p less than 0.001) than did the long-term component (p less than 0.01).

PIP: Intervillous placental blood flow and indices of fetal heart rate variability were measured from 7 healthy pregnant women in the last trimester of pregnancy, once before and twice after smoking 1 cigarette. Mean age was 27.3 years. The mothers were lying in 15 degrees left lateral recumbent position during the experiment. In 7 measurements a blood flow reduction equal to or more than 10% was seen. In 6 cases it was induced by smoking. Intervillous placental blood flow decreased from 93 +or- 11 (SD) to 74 +or- 10 ml/minute/100 ml intervillous blood volume. In 5 measurements an intervillous blood flow rise equal to over 10% was observed. In these cases intervillous placental blood flow increased from 79 +or- 23 to 98 +or- 23 ml. No correlation was observed between the absolute values of intervillous placental blood flow and the means of fetal heart rate variability indices. The main finding was that differential index and interval index correlated significantly with both decreasing and increasing intervillous placental blood flows. This study supports the hypothesis that the decrease of differential index is due to fetal hypoxia, possibly mediated by intervillous placental blood flow decrease, and that the decrease of interval index is due to a direct narcotic effect.

Midtrimester fetal heart rate variability and maternal hemodynamics in association with smoking.

Maternal heart rate (MHR), blood pressure (BP), the differential index (DI) describing the short-term component of fetal heart rate (FHR) variability, and the interval index (II) describing the long-term component were measured in eight subjects in the midtrimester before, during, and after the mothers smoked a standard cigarette. The analyses of FHR variability were performed by an "on-line" method with an abdominal fetal electrocardiogram used as a triggering signal and with a sample time of 1 minute. An increase of MHR, FHR, and BP with a concomitant decrease of II was observed. Unlike our findings regarding the third trimester, no significant change of DI was observed. A correlation analysis revealed fetomaternal hemodynamic relationships different from those in the third trimester: There was a negative correlation between DI and FHR (p less than 0.01) and between DI and MHR (p less than 0.01). There was a positive correlation between FHR and MHR (p less than 0.001). Unlike our findings regarding the third trimester, no correlation was found between DI and BP or between II and MHR. We suggest that the midtrimester fetus shows the narcotic effect (decrease of II) of one cigarette, as does the term fetus, but fails to show the hypoxic effect (decrease of DI), which has been observed in the term fetus.