Differential metabolism of human VLDL according to content of ApoE and ApoC-III.

We studied the metabolism of very low density lipoprotein (VLDL) and intermediate density lipoprotein (IDL) particles that did or did not have apolipoprotein E (apoE) in 12 normolipidemic women by endogenously labeling plasma apolipoprotein B. The plasma was separated into bound (E+) and unbound (E-) fractions by use of a monoclonal antibody (1D7), and the fractions were ultracentrifuged to yield E+ and E- subfractions of light and dense VLDL and IDL. VLDL E+ and IDL E+ were produced mainly by the liver. VLDL E+ and IDL E+ had lower fractional catabolic rates and much higher apolipoprotein C-III (apoC-III) content than did the corresponding E- particles. Most light VLDL apoE+ underwent lipolysis to dense VLDL E+ with reduced apoC-III content, which was removed from the circulation without conversion to IDL. In contrast, most light VLDL apoE-, poor in apoC-III, was removed from the circulation, and a smaller proportion underwent lipolysis to dense VLDL E-. Most dense VLDL E- underwent lipolysis to IDL E-. The rate constant for lipolysis of dense VLDL to IDL was greater for E- than for E+, and the rate constant for clearance from plasma was greater for dense VLDL E+ than for E-. In conclusion, metabolism of human VLDL particles is influenced by their content of apoE, further modulated by the coexistence of apoC-III.

Effects of raloxifene and hormone replacement therapy on markers of serum atherogenicity in healthy postmenopausal women.

OBJECTIVE: To determine the effect of raloxifene (RLX) and hormone replacement therapy (HRT) on non-high density lipoprotein cholesterol (non-HDL-C) levels and the apolipoprotein-B/apolipoprotein-A1 (apo-B/apo-A1) concentration ratio, markers of serum atherogenicity, in postmenopausal women. METHODS: Three hundred and ninety healthy postmenopausal women aged 45-72 years were enrolled in a double-blind, randomized, placebo-controlled, parallel trial at eight outpatient sites in the United States. Women were randomly assigned to receive continuous combined HRT (0.625 mg/day conjugated equine estrogen and 2.5 mg/day medroxyprogesterone acetate), 60 or 120 mg/day raloxifene, or placebo for 6 months. Serum concentrations of non-HDL cholesterol and the apo-B/apo-A1 concentration ratio were measured in serum samples obtained at baseline and at 6 months of treatment. RESULTS: At 6 months, non-HDL-C and apo-B/apo-A1 were significantly reduced by 60 mg/day RLX (10 and 11%, respectively), 120 mg/day RLX (9 and 12%, respectively) and HRT (10 and 12%, respectively), compared with placebo. The effect of all treatments to lower non-HDL-C and apo-B/apo-A1 was greatest in women with hypercholesterolemia (total-C>240 mg/dl) at baseline. Among women with undesirable (>160 mg/dl) non-HDL cholesterol at baseline, RLX and HRT lowered the percentage of these women remaining above this threshold after 6 months (placebo, 89%; 60 mg/day RLX, 61%; 120 mg/day RLX, 74%; HRT, 58%). Similar results were observed for women with high (>190 mg/dl) non-HDL cholesterol at baseline. CONCLUSION: In healthy postmenopausal women, RLX and HRT lower serum non-HDL-C and apo-B/apo-A1, indicators of serum atherogenicity, to a similar extent.

The effects of estrogen and selective estrogen receptor modulators on cardiovascular risk factors.

Raloxifene, a selective estrogen receptor modulator, favorably alters several markers of cardiovascular risk in healthy postmenopausal women. While many of its effects are similar to those of conventional hormone replacement therapy (HRT), there are also important differences. Raloxifene lowered low-density lipoprotein cholesterol levels similarly to estrogen. However, raloxifene lacked the potentially beneficial effects of HRT on high-density lipoprotein cholesterol levels and plasminogen activation inhibitor-1, as well as the potentially adverse effects of HRT on triglycerides and C-reactive protein. Raloxifene also had a potentially beneficial fibrinogen-lowering effect not seen with conventional HRT. The net effect of these differences is unclear. Proof that raloxifene or HRT reduces the risk of heart disease must await the results of ongoing clinical trials with cardiovascular event end points.

Comparison of alendronate and intranasal calcitonin for treatment of osteoporosis in postmenopausal women.

This study compared the effects of oral alendronate and intranasal calcitonin for treatment of osteoporosis in postmenopausal women. Women at least 5 yr postmenopause (n = 299) were randomized to either 10 mg alendronate, matching alendronate placebo, or open-label intranasal calcitonin 200 IU daily for 12 months. Hip and spine bone mineral density (BMD) and markers of bone turnover were measured, and safety and tolerability were assessed. Alendronate produced greater increases in BMD than calcitonin at 12 months at the lumbar spine (5.16% vs. 1.18%; P < 0.001), trochanter (4.73% vs. 0.47%; P < 0.001), and femoral neck (2.78% vs. 0.58%; P < 0.001). Changes in BMD with calcitonin were greater than with placebo at the femoral neck, but were not different from placebo at either the trochanter or lumbar spine. Greater decreases in bone turnover were seen with alendronate than with calcitonin (serum bone-specific alkaline phosphatase, 43% vs. 9%, P < 0.001; urinary N-telopeptide, 62% vs. 11%, P < 0.001). Similar percentages of patients in each group reported an adverse experience during the study. We conclude that, in postmenopausal women with osteoporosis, 12 months of therapy with alendronate produced significantly greater increases in BMD of the hip and spine and greater decreases in bone turnover than intranasal calcitonin.

A 12-month comparative study of raloxifene, estrogen, and placebo on the postmenopausal endometrium.

OBJECTIVE: To determine the effects of a selective estrogen receptor modulator, raloxifene, on postmenopausal endometrium. METHODS: Healthy postmenopausal women (n = 415) were randomly assigned to one of the following four groups: 60 or 150 mg/day raloxifene hydrochloride, 0.625 mg/day conjugated equine estrogens, or placebo, and treated for 1 year. Endometrial biopsies were obtained in a blinded fashion at baseline and every 6 months after the ultrasound studies. Transvaginal ultrasound, with uterine size measurements, was done at baseline and at 3-month intervals. Saline-infusion sonohysterography was done at baseline and every 6 months. RESULTS: There were no statistically significant differences in baseline characteristics. Mean endometrial thickness, measured by transvaginal ultrasound, was unchanged from baseline to end point in the placebo and raloxifene groups, whereas in the estrogen group it was significantly thicker by 5.5 mm (P < .001). Mean uterine volume, calculated from transvaginal ultrasound measurements, was higher in the estrogen group only (22 cm3, P < .001). Of the 358 women with paired biopsies, endometrial hyperplasia was present in 2.1%, 0%, and 26.1% of the end-point biopsies in the placebo, raloxifene, and estrogen groups, respectively (P < .001). Proliferative endometrium was present in 2.1% of the end-point biopsies in the placebo group, 1.7% in the combined raloxifene groups, and 39.8% in the estrogen group (P < .001). CONCLUSION: Raloxifene, at 60 or 150 mg/day for 1 year, did not stimulate the postmenopausal endometrium. End-point endometrial thickness, morphology, and uterine volume in the raloxifene groups were similar to those observed at baseline and in the placebo group.

The effects of hormone replacement therapy and raloxifene on C-reactive protein and homocysteine in healthy postmenopausal women: a randomized, controlled trial.

C-Reactive protein and homocysteine are independent risk factors for the development of cardiovascular disease. This study compared the effects of hormone replacement therapy (HRT) and raloxifene on serum C-reactive protein and homocysteine levels as markers of cardiovascular risk in healthy postmenopausal women. Healthy postmenopausal women (n = 390) were enrolled in a double blind, randomized, placebo-controlled, 6-month trial at eight out-patient sites in the United States. Women were randomly assigned to receive continuous combined HRT (0.625 mg/day conjugated equine estrogen and 2.5 mg/day medroxyprogesterone acetate), raloxifene (60 or 120 mg/day), or placebo for 6 months. C-Reactive protein and homocysteine were measured in baseline and 6-month serum samples. HRT increased C-reactive protein levels by 84% (P<0.001), whereas raloxifene (60 and 120 mg/day) had no significant effect (-6% and -4%;, respectively; P>0.2). Raloxifene (60 and 120 mg/day) significantly lowered serum levels ofhomocysteine by 8% (P = 0.014) and 6% (P = 0.024), respectively, similar to the 7% (P = 0.014) reduction obtained with HRT. We conclude that HRT and raloxifene lower serum homocysteine levels to a comparable extent in postmenopausal women. Whereas cardiovascular risk predicted by C-reactive protein in healthy postmenopausal women is not influenced by raloxifene, the relationship between elevated C-reactive protein levels with HRT and cardiovascular disease events requires further study.

Addition of alendronate to ongoing hormone replacement therapy in the treatment of osteoporosis: a randomized, controlled clinical trial.

Alendronate and estrogen are effective therapies for postmenopausal osteoporosis, but their efficacy and safety as combined therapy are unknown. The objective of this study was to evaluate the addition of alendronate to ongoing hormone replacement therapy (HRT) in the treatment of postmenopausal women with osteoporosis. A total of 428 postmenopausal women with osteoporosis, who had been receiving HRT for at least 1 yr, were randomized to receive either alendronate (10 mg/day) or placebo. HRT was continued in both groups. Changes in bone mineral density (BMD) and biochemical markers of bone turnover were assessed. Compared with HRT alone, at 12 months, alendronate plus HRT produced significantly greater increases in BMD of the lumbar spine (3.6% vs. 1.0%, P < 0.001) and hip trochanter (2.7% vs. 0.5%, P < 0.001); however, the between-group difference in BMD at the femoral neck was not significant (1.7% vs. 0.8%, P = 0.072). Biochemical markers of bone turnover (serum bone-specific alkaline phosphatase and urine N-telopeptide) decreased significantly at 6 and 12 months with alendronate plus HRT, and they remained within premenopausal levels. Addition of alendronate to ongoing HRT was generally well tolerated, with no significant between-group differences in upper gastrointestinal adverse events or fractures. This study demonstrated that, in postmenopausal women with low bone density despite ongoing treatment with estrogen, alendronate added to HRT significantly increased bone mass at both spine and hip trochanter and was generally well tolerated.

Estradiol with or without progesterone and ambulatory blood pressure in postmenopausal women.

The purpose of this study was to determine whether transdermal estradiol and intravaginal progesterone given in doses to mimic the premenopausal state would lower blood pressure (BP) in postmenopausal women. Fifteen healthy postmenopausal women were studied in each of 3 conditions: on placebo, after 8 weeks of transdermal estradiol 0.2 mg twice per week, and again 2 weeks after addition of intravaginal progesterone 300 mg/d. Women were studied at each point after 2 days of 100 mmol/d sodium intake. Twenty-four-hour ambulatory BP monitoring was performed, and blood was assayed for estradiol, progesterone, and hormones of the renin-angiotensin-aldosterone system (RAAS). ANOVA with pairwise comparisons was used for analysis. Urinary sodium excretion was similar at each time point. Levels of estrogen and progesterone similar to those in premenopausal women were achieved. On estradiol, nocturnal systolic BP (110+/-3 mm Hg), diastolic BP (63+/-2 mm Hg), and mean BP (77+/-2 mm Hg) fell significantly (P<0.02) compared with placebo systolic BP (116+/-2 mm Hg), diastolic BP (68+/-2 mm Hg), and mean BP (82+/-2 mm Hg). Daytime BP followed the same trend but was significantly lower only for mean BP. There was no activation of the RAAS. The addition of progesterone resulted in no further fall in BP but a significant activation of the RAAS. Thus, contrary to what is often assumed, administration of estradiol with or without progesterone not only did not raise BP but rather substantially lowered BP. This BP-lowering effect may be responsible for the lower incidence of hypertension in premenopausal than in postmenopausal women.

Relationship between serum estradiol levels and the increases in high-density lipoprotein levels in postmenopausal women treated with oral estradiol.

Postmenopausal women are prescribed a standard dose of estrogen, which is optimal for a population but not for all individuals. We wished to identify if an individual's estradiol level can indicate the minimum effective dose of estrogen which maximally increases high-density lipoprotein (HDL) levels, which could be cardioprotective. We performed a prospective, double-blind crossover study in 19 healthy postmenopausal women, receiving three treatments in random order for 9 weeks each: a) placebo, b) 1 mg oral estradiol daily, and c) 2 mg oral estradiol daily. Lipoprotein and estradiol (E2) levels were measured 10-12 h after pills were taken. E2 levels with 1 mg estradiol were positively correlated with the increases in HDL levels (r = 0.70, P < 0.01). Only the eight subjects who had E2 levels < 50 pg/mL after 1 mg estradiol treatment demonstrated further increases in HDL levels by increasing the daily dose to 2 mg (by 3 +/- 5% with 1 mg estradiol and by 13 +/- 7% with 2 mg). The other 11 subjects who had E2 levels > 50 pg/mL with 1 mg estradiol had no additional benefit from increasing the estradiol dose (HDL increased by 13 +/- 9% with 1 mg, and by 17 +/- 10% with 2 mg). Thus, measurement of an E2 level the morning after taking 1 mg estradiol at bedtime identifies who may benefit from improvement in HDL levels by increasing to a 2-mg dose.

Metabolism of Apo(a) and ApoB100 of lipoprotein(a) in women: effect of postmenopausal estrogen replacement.

The metabolism in plasma of apo(a) and apoB100, the major protein components of lipoprotein(a) [Lp(a)], and the mechanism by which estrogen lowers Lp(a) concentration are both not well understood. Estrogen or placebo were administered to 12 postmenopausal women in a double-blind cross-over design; and after each treatment, apo(a) and apoB100 in Lp(a) were endogenously labeled by i.v. trideuterated leucine. After estrogen treatment, mean Lp(a) concentration decreased during estrogen, from 25 mg/dL, by 20% (P < 0.01); and the mean production rate of apo(a) decreased, from 0.31 nmol/kg.day, by 34% (P = 0.046). In contrast, the mean fractional catabolic rates of apo(a) were similar, 0.36 vs. 0.31/day (P = 0.23). In 6 women, the kinetics of apo(a) and apoB100, the two major proteins of Lp(a), were studied during estrogen and placebo periods. During both periods, the rate of appearance of tracer was similar in Lp(a)-apo(a) and Lp(a)-apoB100, as were the resulting metabolic rates and the changes during estrogen treatment. In conclusion, the findings are more compatible with intracellular synthesis of Lp(a) from nascent apo(a) and apoB100 than extracellular assembly from plasma low-density lipoproteins. Reduced flux into plasma of Lp(a), an atherogenic lipoprotein, could contribute to the lower cardiovascular disease rates in women receiving estrogen replacement therapy.

Estradiol therapy combined with progesterone and endothelium-dependent vasodilation in postmenopausal women.

BACKGROUND: Epidemiological studies indicate that estrogen replacement therapy decreases the risk of cardiovascular events in postmenopausal women. Estrogen may confer cardiovascular protection by improving endothelial function because it increases endothelium-dependent vasodilation. It is not known whether progesterone attenuates the beneficial effects of estrogen on endothelial function. METHODS AND RESULTS: Seventeen postmenopausal women with mild hypercholesterolemia were enrolled in a placebo-controlled, crossover trial to evaluate the effect of transdermal estradiol, with and without vaginal micronized progesterone, on endothelium-dependent vasodilation in a peripheral conduit artery. Brachial artery diameter was measured with high-resolution B-mode ultrasonography. To assess endothelium-dependent vasodilation, brachial artery diameter was determined at baseline and after a flow stimulus induced by reactive hyperemia. To assess endothelium-independent vasodilation, brachial artery diameter was measured after administration of sublingual nitroglycerin. During estradiol therapy, reactive hyperemia caused an 11.1+/-1.0% change in brachial artery diameter compared with 4. 7+/-0.6% during placebo therapy (P<0.001). Progesterone did not significantly attenuate this improvement. During combined estrogen and progesterone therapy, flow-mediated vasodilation of the brachial artery was 9.6+/-0.8% (P=NS versus estradiol alone). Endothelium-independent vasodilation was not altered by estradiol therapy, either with or without progesterone, compared with placebo. There was a modest decrease in total and LDL cholesterol during treatment both with estradiol alone and when estradiol was combined with progesterone (all P<0.001 versus placebo). In a multivariate analysis that included serum estradiol, progesterone, total and LDL cholesterol concentrations, blood pressure, and heart rate, only the estradiol level was a significant predictor of endothelium-dependent vasodilation. CONCLUSIONS: The addition of micronized progesterone does not attenuate the favorable effect of estradiol on endothelium-dependent vasodilation. The vasoprotective effect of hormone replacement therapy may extend beyond its beneficial actions on lipids.

Thermal balloon and rollerball ablation to treat menorrhagia: a multicenter comparison.

OBJECTIVE: To compare the clinical efficacy and safety of a thermal uterine balloon system with hysteroscopic rollerball ablation in the treatment of dysfunctional uterine bleeding. METHODS: Two hundred fifty-five premenopausal women were treated in a randomized multicenter study comparing thermal uterine balloon therapy with hysteroscopic rollerball ablation for the treatment of menorrhagia. Preprocedural and postprocedural menstrual diary scores and quality-of-life questionnaires were obtained. Twelve-month follow-up data are presented on 239 women. RESULTS: Twelve-month results indicated that both techniques significantly reduced menstrual blood flow with no clinically significant difference between the two groups as reflected by return to normal bleeding or less (balloon 80.2% and rollerball ablation 84.3%). Multiple quality-of-life questionnaire results were also similar, including percent of patients highly satisfied with their results (balloon 85.6% compared with rollerball 86.7%). A 90% decrease in diary scores was seen in more than 60% of patients in both groups. Procedural time was reduced significantly in the uterine balloon therapy group. Intraoperative complications occurred in 3.2% of the hysteroscopic rollerball patients, whereas no intraoperative complications occurred in the thermal balloon group. CONCLUSION: In the treatment of dysfunctional uterine bleeding, uterine balloon therapy is as efficacious as hysteroscopic rollerball ablation and may be safer.

Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women.

CONTEXT: Raloxifene is a selective estrogen receptor modulator that has estrogen-agonistic effects on bone and estrogen-antagonistic effects on breast and uterus. OBJECTIVE: To identify the effects of raloxifene on markers of cardiovascular risk in postmenopausal women, and to compare them with those induced by hormone replacement therapy (HRT). DESIGN: Double-blind, randomized, parallel trial. SETTING: Eight sites in the United States. PARTICIPANTS: 390 healthy postmenopausal women recruited by advertisement. INTERVENTION: Participants were randomized to receive 1 of 4 treatments: raloxifene, 60 mg/d; raloxifene, 120 mg/d; HRT (conjugated equine estrogen, 0.625 mg/d, and medroxyprogesterone acetate, 2.5 mg/d); or placebo. MAIN OUTCOME MEASURES: Change and percent change from baseline of lipid levels and coagulation parameters after 3 months and 6 months of treatment. RESULTS: At the last visit completed, compared with placebo, both dosages of raloxifene significantly lowered low-density lipoprotein cholesterol (LDL-C) by 12% (P < .001), similar to the 14% reduction with HRT (P < .001). Both dosages of raloxifene significantly lowered lipoprotein(a) by 7% to 8% (P < .001), less than the 19% decrease with HRT (P<.001). Raloxifene increased high-density lipoprotein-2 cholesterol (HDL2-C) by 15% to 17% (P < .05), less than the 33% increase with HRT (P < .001). Raloxifene did not significantly change high-density lipoprotein cholesterol (HDL-C), triglycerides, or plasminogen activator inhibitor-1 (PAI-1); whereas HRT increased HDL-C by 11% and triglycerides by 20%, and decreased PAI-1 by 29% (for all, P < .001). Raloxifene significantly lowered fibrinogen by 12% to 14% (P < .001), unlike HRT, which had no effect. Neither treatment changed fibrinopeptide A or prothrombin fragment 1 and 2. CONCLUSIONS: Raloxifene favorably alters biochemical markers of cardiovascular risk by decreasing LDL-C, fibrinogen, and lipoprotein(a), and by increasing HDL2-C without raising triglycerides. In contrast to HRT, raloxifene had no effect on HDL-C and PAI-1, and a lesser effect on HDL2-C and lipoprotein(a). Further clinical trials are necessary to determine whether these favorable biochemical effects are associated with protection against cardiovascular disease.

Fibrinolytic potential is significantly increased by oestrogen treatment in postmenopausal women with mild dyslipidaemia.

OBJECTIVE: To study the effects of oestrogen replacement treatment on fibrinolytic potential in postmenopausal women. DESIGN: Randomised, double blind, placebo controlled trial of oral 17 beta-oestradiol. SETTING: Subjects were evaluated in the outpatient setting. PATIENTS: Nineteen postmenopausal women with mild dyslipidaemia, aged 44 to 69 years (mean (SD) 55.7 (6.7)). MAIN OUTCOME MEASURES: Fibrinolytic activity (fibrin plate assay) and tissue plasminogen activator (t-PA) antigen were measured at baseline and after three, six, and nine weeks of each treatment. RESULTS: After nine weeks of 2 mg oestradiol treatment, there was a significant increase in fibrinolytic potential compared with placebo, as indicated by an increase in fibrinolytic activity (mean (SEM), 80 (9) v 54 (5) mm2 of lysis in the fibrin plate, 2 mg v placebo, p = 0.002) and a decrease in t-PA antigen (5.8 (0.9) v 8.4 (1.2) ng/ml, 2 mg v placebo, p < 0.001). There was a similar trend with the 1 mg dose but the changes were less noticeable. CONCLUSIONS: Hormone replacement treatment with 17 beta-oestradiol for nine weeks significantly increased fibrinolytic potential in postmenopausal women with mild dyslipidaemia. This suggests that the cardioprotective effect of oestrogen may be mediated, in part, by an increase in fibrinolytic potential.

Effect of estrogen on very low density lipoprotein and low density lipoprotein subclass metabolism in postmenopausal women.

Estrogen decreases low density lipoprotein (LDL) particle size, and smaller LDL particles are associated with coronary atherosclerosis. To understand the metabolic basis for this change, we studied the effect of oral 17 beta-estradiol (2 mg/day) on apolipoprotein B-100 (apoB) metabolism, in eight healthy postmenopausal women. The study was a randomized, double blinded, placebo-controlled, cross-over trial with intervention sequences of 6 weeks each. ApoB in very low density lipoprotein, intermediate density lipoprotein, and LDL subclasses was endogenously labeled with [D3]L-leucine, and metabolic rates were calculated by computer modeling. The overall effect of oral estrogen therapy on apoB metabolism was to accelerate the fractional catabolic rates of all particles studied and production rates of all except IDL. For light LDL (density = 1.019-1.036 g/mL), estrogen increased the mean fractional catabolic rate by 63% from 0.59 to 0.96 pools/day (P = 0.02), whereas the production rate increased by a lesser amount (42%) from 575 to 817 mg/day (P = 0.10). These metabolic changes reduced light LDL cholesterol and apoB concentrations by 26% (P = 0.005) and 19% (P = 0.03), respectively. In contrast, dense LDL (density = 1.036-1.063 g/mL) cholesterol and apoB concentrations were unchanged by the intervention, as both the apoB fractional catabolic rate and production rate were significantly increased by similar amounts, 39% (from 0.41 to 0.57 pools/day, P = 0.01) and 38% (from 434 to 601 mg/day; P = 0.003), respectively. Estrogen decreased the predominant LDL peak particle size from 273 to 268 A (P = 0.04). Thus, estrogen therapy increases the clearance of both light and dense LDL, counteracting increases in production rates. The reduced plasma residence times of light and dense LDL both may be antiatherogenic, even though, for dense LDL, the concentration did not change.

Estrogen absorption and metabolism in postmenopausal women with end-stage renal disease.

Women with end-stage renal disease (ESRD) have a higher rate of death from heart disease than women with normal renal function. Because estrogen replacement therapy may significantly decrease the incidence of death due to cardiovascular disease in postmenopausal women with normal renal function, their use has been considered for women with ESRD. However, the pharmacokinetics of estrogen have not been studied in postmenopausal women with ESRD to determine the optimal estrogen dose. Six postmenopausal women with ESRD receiving maintenance hemodialysis and six controls matched for body mass index were admitted to the in-patient Clinical Research Center. A 1- or 2-mg oral estradiol (E2) pill was given while subjects fasted. Blood sampling was performed over the next 24 h for measurement of E2, estrone (E1), albumin, and sex hormone-binding globulin (SHBG). Three weeks later, the subjects were given the other E2 dose under identical conditions. At baseline, total and free E2 levels were higher in the subjects with ESRD than in controls (P = 0.0005 and 0.0035, respectively). After ingestion of 1 and 2 mg E2, total and free E2 levels remained significantly higher in the ESRD subjects from 2-8 h after treatment (P < or = 0.05). After 1 mg oral E2, total serum E2 peaked at 65 pg/mL at 4 h in ESRD subjects and at 27 pg/mL in control subjects at 8 h. After 2 mg oral E2 treatment, total serum E2 peaked at 8 h in both ESRD and control subjects, with levels of 99 and 37 pg/mL, respectively. E1 was higher in the subjects with ESRD than in the control subjects at baseline (P < 0.05). After ingestion of 1 mg E2, E1 concentrations were not significantly higher in ESRD than in control subjects, peaking at 180 and 121 pg/mL, respectively (P = 0.3). E1 concentrations were higher in ESRD than in control subjects after the ingestion of 2 mg E2, with peak levels of 376 and 201 pg/mL, respectively (P = 0.03). Total and free E2 levels are higher in patients with ESRD than in control subjects at baseline and after E2 ingestion, indicating that renal failure alters the pharmacokinetics of both endogenous and exogenous E2. Therefore, conventional E2 doses used in individuals with normal renal function may be excessive for patients with ESRD.

The effects of ethanol on the clearance of estradiol in postmenopausal women.

OBJECTIVE: To determine whether acute alcohol ingestion affects the pattern of decline of circulating E2 levels after removal of transdermal E2 patches. DESIGN: A randomized, placebo-controlled, crossover study. SETTING: The study was performed in the Clinical Research Center of the Brigham and Women's Hospital. PARTICIPANTS: Twelve healthy postmenopausal women were enrolled. INTERVENTIONS: Transdermal E2 patches, 0.15 mg, were applied 13 hours before subjects ingested alcohol (1 mL/kg 95% ethanol) or carbohydrate placebo punch. The patches were removed immediately after drink ingestion. MAIN OUTCOME MEASURES: Estradiol, estrone (E1), and ethanol levels were measured. RESULTS: Serum samples were obtained for 40 minutes before drink ingestion and 5 hours after drink ingestion and E2 patch removal. At the time of patch removal, E2 levels rose acutely over 10 minutes and then decreased rapidly, suggesting a bolus effect that was more marked after ethanol ingestion. After ethanol ingestion and patch removal the half-life of E2 was calculated to be 378 minutes, and after carbohydrate punch and patch removal 245 minutes. There were no significant changes in E1 concentrations over the time course of the study between groups. CONCLUSIONS: Ethanol ingestion may decrease E2 clearance after removal of transdermal E2 patches.

Sex hormones, lipoproteins, and vascular reactivity.

The HDL-raising effect of estrogen replacement is mediated by an increase in HDL-apolipoprotein A-I production and not by a decrease in the clearance rate. Large-scale clinical trials have shown that medroxyprogesterone acetate removes most of the HDL-raising effects of concomitant estrogen treatment. Testosterone decreases HDL levels in both men and women. Lipoprotein (a) levels are reduced by estrogen replacement, but are not affected by medroxyprogesterone. The acute systemic administration of estrogen to postmenopausal women improves the endothelium-dependent vasodilation of coronary arteries and forearm resistance vessels. Usual doses of oral estrogen replacement therapy improve the endothelium-dependent and endothelium-independent vasodilator responses in the forearm in women who have risk factors for atherosclerosis. These effects may be mediated by an antioxidant action of estrogen.