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.

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.

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.

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.

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.

Stress hormones and placental steroids in physical exercise during pregnancy.

The hormonal responses to exercise during later pregnancy were studied in relation to an exercise test in ten healthy women. At the end of the 10-min exercise, maternal heart rate had risen from 93 +/- 3.2 (mean +/- SEM) to 157 +/- 6.3 beats/min, and systolic blood pressure from 120 +/- 3.4 to 148 +/- 5.4 mmHg, but diastolic blood pressure was unchanged. Plasma concentrations of noradrenaline and adrenaline rose rapidly during the exercise, from 2.9 +/- 0.3 to 6.9 +/- 1.2 nmol/l and from 0.31 +/- 0.04 to 0.47 +/- 0.08 nmol/l respectively. The serum concentration of prolactin did not change during the test, but 30 min after the exercise the value had risen from 146 +/- 17 to 212 +/- 22 mg/ml, thereafter slowly declining. The serum concentration of cortisol remained unchanged. The mean concentration of oestriol rose from 31.5 +/- 2.6 to 33.9 +/- 3.0 nmol/l at least 5 min after the exercise, thereafter declining to 29 +/- 2.6 nmol/l. After the test, levels of progesterone and oestradiol also fell slightly. Mild irregular uterine activity was found in four subjects. Cardiotocography revealed a transient fetal tachycardia in two subjects.

Significant correlation between maternal hemodynamics and fetal heart rate variability.

The differential index, describing the short-term component, and the interval index, describing the long-term component, of fetal heart rate variability were measured by an on-line method from the abdominal electrocardiograms of eight fetuses during the third trimester of normal pregnancies while mothers were smoking a cigarette. Maternal heart rate and maternal blood pressure were measured intermittently before, during, and after smoking. Analyses of fetal heart rate variability were performed continuously with the sample time of 1 minute during the experiments. An increase in maternal heart rate and blood pressure, with concomitant decrease in the interval index and the differential index, was observed. The correlation analysis revealed a negative correlation between maternal heart rate and the interval index (p less than 0.001), between diastolic pressure and the differential index (p less than 0.01), and between systolic pressure and the differential index (p less than 0.01).