Intrauterine 10 microg and 20 microg levonorgestrel systems in postmenopausal women receiving oral oestrogen replacement therapy: clinical, endometrial and metabolic response.

OBJECTIVE: The clinical and endometrial efficacy and lipid response of two different doses of intrauterine levonorgestrel were assessed in comparison with sequential oral medroxyprogesterone acetate in postmenopausal women receiving continuous oral E2-valerate. DESIGN: One-year prospective multicentre randomised control trial. SETTING: Four outpatient clinics in Oulu, Helsinki and Jyväskylä, Finland. POPULATION: A total of 163 healthy volunteer postmenopausal women with climacteric complaints or already using hormone replacement therapy (HRT). INTERVENTIONS: Subjects were randomly allocated to receive a new intrauterine system releasing 10 microg of levonorgestrel daily or an established intrauterine system (Mirena) releasing 20 microg of levonorgestrel daily or sequential oral medroxyprogesterone acetate (5mg/day, 14/30 days). All three regimens were combined with an oral daily dose of 2mg of E2-valerate. MAIN OUTCOME MEASURES: Bleeding patterns were assessed by diaries kept by the subjects. Endometrial effects were evaluated by histologic biopsies taken at the baseline and after six and 12 months of therapy. Serum concentrations of total, HDL and LDL cholesterol, triglycerides and lipoprotein(a) were determined at the baseline and after six and 12 months of therapy. RESULTS: Insertion of the smaller 10 microg levonorgestrel system was easy in 70% and difficult in 4% and that of Mirena was easy in 46% and difficult in 21% of the subjects. After six months of therapy, 43 (95.6%) of the 47 subjects receiving 10 microg levonorgestrel and 54 (98.2%) of the 55 subjects receiving 20 microg levonorgestrel had no bleeding, while the sequential medroxyprogesterone acetate regimen produced typical cyclic withdrawal bleedings. Endometrial hyperplasia was not observed in any of the treatment groups during the 12-month study. After 12 months of therapy, strong endometrial suppression was found in 46/47 and 55/55 of the subjects receiving 10 microg and 20 microg of levonorgestrel, respectively, while the endometrium was proliferative in 18/47 of the subjects in the medroxyprogesterone acetate group. Serum total cholesterol decreased in all treatment groups. HDL cholesterol increased in women receiving medroxyprogesterone acetate or the smaller intrauterine dose of levonorgestrel. CONCLUSIONS: Both intrauterine doses of levonorgestrel provided good endometrial protection in postmenopausal women on oestrogen replacement therapy. The advantage of the 10 microg system with a smaller size is the easier insertion of the system and a minimal attenuation of the favourable effects of oral oestrogen on the serum lipid profile.

Responses of HDL subclasses, Lp(A-I) and Lp(A-I:A-II) levels and lipolytic enzyme activities to continuous oral estrogen-progestin and transdermal estrogen with cyclic progestin regimens in postmenopausal women.

Seventy postmenopausal women took part in the study. Subjects received either continuous oral 17 beta-estradiol 2 mg/day combined with norethisterone acetate 1 mg/day (E2/NETA, Kliogest) or transdermal treatment consisting of 28 day cycles with patches delivering 17 beta-estradiol 50 micrograms/day (Estraderm) combined with cyclic medroxyprogesterone acetate 10 mg/day (E2/MPA, Provera), on days 17-28. At baseline the serum lipid and lipoprotein concentrations, composition and concentrations of high density lipoprotein (HDL) subclasses, lipoprotein (Lp)(AI) and Lp(A-I:A-II) levels were comparable in the two groups. In the E2/NETA group, after 12 months hormone replacement therapy (HRT), the HDL2 cholesterol concentration decreased by 17% (P < 0.01) and the HDL3 cholesterol remained unchanged. The concentrations of HDL2b, HDL2a and HDL3a were reduced by 30, 26 and 15%, respectively, P < 0.001, and the cholesterol:triglyceride ratio decreased significantly in all HDL subclasses. Apolipoprotein (apo) A-I concentration decreased by 5% (P < 0.05), but apo A-II, Lp(A-I) and Lp(A-I:A-II) concentrations remained unchanged. In the E2/MPA group the HDL2 and HDL3 cholesterol levels were both reduced by 6% (P < 0.05) and the HDL3a, HDL3b and HDL3c concentrations decreased by 14, 12 and 17% during the E2/MPA phase compared with baseline (P < 0.01). No major changes in the composition of HDL subclasses occurred in the E2 MPA group during treatment. The apo A-I and Lp(A-I) levels were not changed, but apo A-II and Lp(A-I:A-II) concentrations decreased by 8 and 5%, P < 0.001 and P < 0.05, respectively. At 12 months the postheparin plasma hepatic lipase (HL) activity decreased only in the E2/NETA group (by 12%, P < 0.05). The cholesteryl ester transfer protein (CETP) activity was not affected by either HRT regimen. The results of our study show that the 2 HRT regimens have multiple effects on HDL particles and HRT induced changes in HDL are not associated with changes in activities of lipolytic enzymes or CETP.

Different effects of continuous oestrogen-progestin and transdermal oestrogen with cyclic progestin regimens on low-density lipoprotein subclasses.

Seventy-five postmenopausal women were randomly allocated to receive either continuous oral 17 beta-oestradiol 2 mg day-1 and norethisterone acetate 1 mg day-1 (E2/NETA) or transdermal treatment consisting of 28-day cycles with patches delivering 17 beta-oestradiol 50 micrograms day-1 combined with oral cyclic medroxyprogesterone acetate 10 mg day-1, on days 17-28 (E2/MPA). At baseline, the plasma lipid and lipoprotein concentrations, composition and concentrations of low-density lipoprotein (LDL) subclasses (LDL1, LDL2 and LDL3) isolated by density-gradient ultracentrifugation were similar in the two groups. The post-heparin plasma hepatic lipase activity (HL) correlated inversely with the percentage of total LDL found in LDL1 (buoyant LDL) and directly with the percentage of LDL found in LDL3 (dense LDL). After 12 months of hormone replacement therapy (HRT), the total and LDL-cholesterol concentration of the E2/ NETA group decreased by 14% and 17% respectively (P < 0.001), while in the E2/MPA group these parameters remained unchanged. The lowering of LDL-cholesterol in the E2/NETA group was a consequence of a significant reduction of the large, buoyant LDL particles (LDL1) from 103 mg dL-1 to 60 mg dl-1 (P < 0.001) and of a decrease of cholesterol content of LDL particles in the major LDL subclass, LDL2. In the E2/MPA group, the concentration of LDL1 decreased, but less than in the oral group. In both groups, a significant increase in the concentration of the LDL3 subclass was observed, indicating an overall shift to denser LDL particles. After 12 months, the post-heparin plasma HL activity decreased only in the E2/NETA group (by 12%). The inverse correlation between post-heparin plasma HL activity and LDL1 persisted in both groups, but the direct correlation between HL and LDL3 vanished in the E2/NETA group and subsided in the E2/MPA group. Our results indicate that HRT has multiple effects on LDL subclasses and suggest that these changes cannot be explained by changes in HL activity.

Hormone replacement therapy lowers plasma Lp(a) concentrations. Comparison of cyclic transdermal and continuous estrogen-progestin regimens.

To study the responses of serum lipoproteins, apoproteins (apo's), and lipoprotein(a) (Lp[a]) to two frequently used hormone replacement therapies (HRTs), 120 postmenopausal women were randomly allocated to receive either transdermal therapy consisting of 28-day cycles with patches that delivered 17 beta-estradiol (50 micrograms/d) combined with cyclic oral medroxyprogesterone acetate (10 mg/d for 12 days per cycle) or continuous oral 17 beta-estradiol (2 mg/d) together with norethisterone acetate (1 mg/d) for 12 months. Blood samples were taken before and at 6 and 12 months of HRT. Concentrations of serum total, low density lipoprotein (LDL) and high density lipoprotein (HDL) cholesterol decreased by 14% (P < .001), 17% (P < .001), and 9% (P < .001) in the oral HRT group. Respective changes were 5.7% (P < .001), 4.8% (P < .05), and 4.7% (NS) in the transdermal group. Serum triglycerides remained unchanged in the oral group but decreased by 15.7% (P < .001) in the transdermal group. We observed only trivial changes in serum apo B levels. The changes in apo A-I levels paralleled those of HDL cholesterol in the oral HRT group. The concentration of serum Lp(a) decreased by 31% (P < .001) and 16% (P < .001) in the two groups. The combination of progestin and transdermal estrogen was not associated with any further change of Lp(a). The decrement in Lp(a) during therapy was positively associated with baseline Lp(a) levels in both groups (r = .96, P < .001 and r = .88, P < .001). Thus, both HRT regimens were highly effective in lowering elevated Lp(a) levels in postmenopausal women. The divergent responses of LDL and HDL cholesterol in the two HRT groups may influence the potential cardioprotective effects of the two HRT regimens. Prospective trials are needed to define the long-term effects with respect to coronary heart disease risk.

Effects of postmenopausal estrogen/progestin replacement therapy on LDL particles; comparison of transdermal and oral treatment regimens.

The aim of the study was to compare the effects of continuous oral estrogen/progestin therapy to the effects of transdermal estrogen therapy combined with cyclic oral progestin on the properties of LDL particles. Eighty postmenopausal women were randomly allocated to receive either oral (continuous 17-beta-estradiol 2 mg and norethisterone acetate 1 mg per day, E2/NETA) or transdermal therapy (patches delivering continuous 17-beta-estradiol, E2, 0.05 mg/day with sequential oral medroxyprogesterone acetate, MPA, 10 mg/day for 12 days/cycle). The groups had similar mean values and ranges of age, BMI and postmenopausal status. The blood samples were taken at baseline, and twice at 1 year before and after MPA administration. LDL particle size distribution was determined by gradient gel electrophoresis and LDL was isolated by sequential ultracentrifugation for compositional analyses. Concentrations of total LDL mass, LDL cholesterol and LDL protein decreased in the oral treatment group (p < 0.01, p < 0.001 and p < 0.01, respectively), whereas they remained unchanged during the transdermal therapy. Particle size of the major LDL peak remained unchanged during both transdermal and oral therapies. HDL cholesterol concentration decreased significantly in both treatment groups (p < 0.001 for both). Serum triglyceride and HDL cholesterol concentrations were the strongest determinants of LDL particle size ( r = -0.50 and r = 0.54, respectively, p < 0.001 for both). The cholesteryl esters and free cholesterol content of the LDL particles decreased in the oral treatment group (p < 0.05). Phospholipid content of LDL increased in both groups receiving either oral or transdermal therapy (p < 0.01 for both). In conclusion, oral administration of 17-beta-estradiol and norethisterone acetate caused a decrease in LDL mass by decreasing the number and cholesterol content of LDL particles. The concomitant decrease of HDL cholesterol by progestins may partly negate this beneficial effect of LDL lowering.

Effects of natural oestrogen/progestogen substitution therapy on carbohydrate and lipid metabolism in post-menopausal women.

Oral glucose tolerance tests were performed in 30 post-menopausal women before and after 1 mth and 6 mth of cyclic 17 beta-oestradiol/norethisterone acetate substitution therapy. Before undergoing treatment the patients were divided into three groups comprising subjects with normal glucose tolerance, subjects with impaired glucose tolerance and diabetic subjects receiving oral diabetic treatment respectively. Carbohydrate metabolism was evaluated during a 2-h oral glucose tolerance test following a 100 g glucose load. Both blood glucose and plasma insulin values were measured. The fasting serum cholesterol and triglyceride levels were also determined. Hormone substitution therapy had no effect on fasting blood glucose values in any of the three groups. At the end of the 6 mth substitution therapy, however, it was found that the blood glucose values in the subjects with impaired glucose tolerance were significantly lowered by the end of the 2-h test period. The glucose areas under the curve during oral glucose tolerance tests following the hormone treatment were also reduced in this same group. In the case of insulin, the areas under the curve remained unchanged in all three groups. Fasting serum cholesterol levels tended to fall, while the triglyceride levels remained unaltered, during the hormone treatment periods. However, a slight increase in triglyceride levels was observed in the subjects with impaired glucose tolerance.

Blood pressure and hemodynamics in postmenopausal women during estradiol-17 beta substitution.

Blood pressure, central hemodynamics and peripheral blood flow were measured at rest in 20 normotensive and 20 hypertensive postmenopausal women during cyclic placebo/estradiol-17 beta treatment. Micronized estradiol-17 beta was given in daily doses of 2 mg and 4 mg. Corresponding measurements were also performed during exercise in 10 borderline hypertensive subjects given estradiol-17 beta substitution in 2 mg daily doses for three months. In addition, electrocardiograms and changes in various hematological parameters were evaluated both at rest and during exercise. Cardiac output was determined by the isotope 113mIn radiocardiographic method, and peripheral blood flow was measured using the vena-occlusion plethysmograph. The serum estrone, estradiol, FSH, LH and prolactin concentrations were determined by radioimmunoassay. Estradiol-17 beta substitution decreased the systolic and diastolic blood pressure in normotensive, hypertensive and borderline hypertensive postmenopausal women. The blood pressure of the hypertensive subjects decreased on average more than the blood pressure of the normotensive subjects. A statistically significant correlation was observed between the increase in serum estrone concentration and the decrease in systolic and diastolic blood pressures produced by the 4 mg daily doses of estradiol-17 beta in the hypertensive subjects. In the borderline hypertensive subjects systolic blood pressure was lower during estradiol-17 beta substitution than before treatment even when measured during exercise. No dose-dependent effect was observed in connection with the decrease in blood pressure. Irrespective of the pretreatment blood pressure levels, heart rate decreased during estradiol-17 beta substitution. The change was most marked in hypertensive and borderline hypertensive women. Estradiol-17 beta treatment did not influence heart rate during exercise. There was a statistically significant correlation between the decrease in resting heart rate and the increase in serum estrone concentration produced by the 4 mg daily doses of estradiol-17 beta in the normotensive subjects. Estradiol-17 beta substitution caused an increase in the blood volume in all groups of postmenopausal women. Estradiol-17 beta substitution with the 2 mg daily dose produced an increase in blood volume, which correlated significantly with the rise in both serum estrone and serum estradiol concentrations. This correlation was observed in both normotensive and hypertensive women. Cardiac output increased in the normotensive test subjects but decreased in the hypertensive and borderline hypertensive subjects.(ABSTRACT TRUNCATED AT 400 WORDS)

Intervillous blood flow in normal and complicated late pregnancy measured by means of an intravenous 133Xe method.

Intervillous blood flow (IVBF) was measured intravenously with a new quantitative 133Xe method in 50 normal and 74 complicated late pregnancies between the 35th and 42nd weeks. The distribution of individual flow rates seemed to be fairly wide in both the normal and the pathological groups. The mean rate of IVBF in normal pregnancies was 140 ml/100 ml of intervillous space/min. The lowest mean flow values were observed in pregnancies complicated by diabetes mellitus (class B-E), cholestasis of pregnancy and severe pre-eclampsia, a highly significant difference (p less than 0.001) from the mean IVBF observed in normal pregnancies. The significance of the results in the different groups has been discussed in detail. This method may open up a new diagnostic area in the management of high-risk pregnancies.

Haemodynamic and hormonal effects of short-term oestradiol treatment in postmenopausal women.

Haemodynamic changes during a 3-wk treatment with oestradiol valerianate (2 mg/day orally) were studied in 12 postmenopausal women by isotope 113Inm radiocardiography. Systolic blood pressure measured in the supine position decreased during oestradiol treatment by 3% (P less than 0.05) and the diastolic blood pressure decreased by 4% (P less than 0.01). The heart rate decreased by 15% (P less than 0.001). Blood volume increased during oestrogen treatment by 5% (P less than 0.05) whereas cardiac output decreased by 9% (P less than 0.05). Stroke volume increased by 13% (P less than 0.001) due to concomitant decrease in heart rate. Changes in plasma oestrone and oestradiol concentrations during oestradiol valerianate substitution showed a positive correlation with the changes of blood volume.

[Uteroplacental blood flow in normal pregnancy before and after short-term treatment with (isoxsuprine) beta-sympathicomimetica (author's transl)]. / Uteroplazentare Perfusion bei normalen Schwangerschaften vor und nach Kurzzeit-Therapie mit (Isoxsuprin) Beta-Sympathiekomimetika.

The uteroplacental blood flow was measured in 26 normal pregnant women between the 36-43 weeks of pregnancy before and after a short-term treatment of isoxsuprine. The patients had no complications of pregnancy and no uterine contractions during this time. We used our intravenous Xe-133 method for measuring the intervillous and myometrial perfusion (20). During the blood flow measurements we also measured maternal arterial blood pressure and heart rate. To evaluate the short-term treatment effect of isoxsurpine we applied an intravenous injection or infusion. The placental flow was (124 +/- 32) before and (117 +/- 39) ml/min/100 ml after isoxsuprine application. The corresponding values for myometrial flow were (7,8 +/- 3,5) and (6,2 +/- 3,0) ml/min/100 g. The pathological changes of the uterplacental blood flow with vena caval syndrom will referred in text. There was a statistically significant increase in maternal heart rate and a decrease in blood pressure.

Measurement of intervillous and myometrial blood flow by an intravenous 133Xe method.

A new 'non-invasive' method for measuring intervillous and myometrial blood flow is presented. After 2 mCi of 133Xe in physiological saline was injected intravenously the patient held her breath for 20 seconds. The tracer entered the placenta as a short bolus and its removal was followed with a scintillation detector. Intervillous and myometrial blood flow per unit volume was calculated from the two-exponential curve. The mean +/-SD intervillous flow in normal pregnancy was 135+/-49 ml/minute/100 ml, the corresponding half time being 0-56+/-0-16 minutes. The myometrial flow was 7-7+/-2-5 ml/minute/100 g. The method gave reproducible results and took only 20 minutes to perform. The dose of radiation to the mother was less than 1 mrad.