Additive effect of alfacalcidol on bone mineral density of the lumbar spine in Taiwanese postmenopausal women treated with hormone replacement therapy and calcium supplementation: a randomized 2-year study

OBJECTIVE: To evaluate the effect of 1alpha-hydroxyvitamin D3 on bone mineral density of the lumbar spine in postmenopausal women receiving hormone replacement therapy and calcium supplement. DESIGN: A randomized, prospective 2-year clinical trial. PATIENTS AND MEASUREMENTS: A total of 240 postmenopausal women were enrolled with randomized assignment of 120 patients to each treatment group (the D + E group of 1alpha-hydroxyvitamin D3 + sequential combined HRT + calcium supplement; the E group: sequential combined HRT + calcium supplement). None of the patients had received HRT for menopausal syndrome or osteoporosis before being enrolled in our study. Serum biochemical assays, electrolytes and calcitonin were performed at baseline and after 6 and 12 months of treatment. Bone mineral density (BMD) of L2-L4 was measured by dual energy X-ray absorptiometry (DXA) at the initial assessment and after 12 and 24 months of treatment. RESULTS: One hundred and five patients (87.5%) in the D + E group and 92 patients (76.7%) in the E group completed the first 1-year study. Ninety-six patients (80%) in the D + E group and 80 patients (66.7%) in the E group completed the 2-year trial. Renal function, liver function, electrolytes and calcitonin showed no significant changes during the first year of follow-up. In the D + E group, the BMD of L2-4 increased 3.24 +/- 0.32% from baseline after 1 year (P < 0.05) and 5.32 +/- 0.23% after 2 years of treatment (P < 0.05). On the other hand, the changes of BMD in the E group were 1.12 +/- 0.34% after 1 year (P < 0.05) and 2.42 +/- 0.26% after 2 years of treatment (P < 0.05). The changes of BMD of L2-L4 of the D + E group were higher than the changes of the E group after both 1 and 2 years of treatment (P < 0.05). CONCLUSIONS: Our study demonstrated that combination of 1alpha-hydroxyvitamin D3 with HRT is superior to HRT alone for the preservation of bone mineral density in postmenopausal women under calcium supplementation.     

Effects of hormone replacement therapy on bone mineral density in postmenopausal women with primary hyperparathyroidism: four-year follow-up and comparison with healthy postmenopausal women

BACKGROUND: Long-term treatment of patients with asymptomatic primary hyperparathyroidism remains controversial, but the presence of osteoporosis is regarded as an indication for parathyroidectomy. Hormone replacement therapy (HRT) is a possible alternative therapy in osteopenic postmenopausal women with the disorder, and results of short-term studies suggest a beneficial effect on bone mass comparable to that achieved by parathyroidectomy. Longer-term data are required to further assess the efficacy of this treatment in chronic stable primary hyperparathyroidism. METHODS: We report the results of the extension from 2 to 4 years of a randomized, placebo-controlled trial of HRT in postmenopausal women with primary hyperparathyroidism. Of 23 postmenopausal women with primary hyperparathyroidism, 11 received active HRT with conjugated equine estrogen, 0.625 mg/d, and medroxyprogesterone acetate, 5 mg/d, and 12 received placebo. Bone mineral density was measured throughout the skeleton at 6-month intervals using dual-energy x-ray absorptiometry in these women and in 50 normocalcemic age-matched control subjects. None of the 23 patients withdrew during the extension period. RESULTS: Changes in bone mineral density were more positive in those taking HRT than placebo, with the between-group differences at 4 years being 4.6% in the total body, 7.5% in the lumbar spine, 7.4% in the femoral neck, 8.2% in the femoral trochanter, 6.8% in the legs, and 7.0% in the forearm (P<.01). At skeletal sites composed predominantly of cortical bone, there was a progressive divergence of the 2 groups. Biochemical markers of bone turnover remained lower throughout the study in women taking HRT. When rates of bone loss were compared between the placebo group and healthy women of comparable age, bone loss tended to be more marked throughout the skeleton in women with hyperparathyroidism, but only in the total body and its legs subregion was this difference significant. CONCLUSIONS: Hormone replacement therapy is efficacious in the long-term management of osteopenia in postmenopausal women with primary hyperparathyroidism and thus represents an important new therapeutic option for asymptomatic patients who do not have other indications for surgery. Bone loss seems to be accelerated in untreated primary hyperparathyroidism.     

The influence of thinness and smoking on bone loss and response to hormone replacement therapy in early postmenopausal women

We studied the influence of thinness and smoking in 153 early postmenopausal women from a 3-yr period, comparing treatments of 1 or 2 mg estradiol with placebo. The baseline body mass index (BMI) was significantly associated with bone resorption (r = -0.26, P < 0.01 for urinary CrossLaps with 21% difference between extreme tertiles) with a consequent association between BMI and bone mineral density (BMD; r = 0.38, P < 0.001 for BMD of hip with 10% difference between extreme tertiles). A low BMI led to an increased rate of loss (r = 0.45, P < 0.01 for BMD of spine), whereas response to treatment with either 1 or 2 mg estradiol was independent of BMI. Smoking was associated with a 4% lower BMD at baseline compared with that in nonsmokers. This effect was additive with that of BMI. For smokers the increase in serum estradiol during hormone replacement therapy was only half of that in nonsmokers. For women treated with placebo or 2 mg estradiol, serum FSH levels were similar in smokers and nonsmokers, but during treatment with 1 mg estradiol, serum FSH was significantly less suppressed in smokers. This was mirrored in the BMD response, where smokers responded similarly to 2 mg estradiol and placebo as did nonsmokers, whereas smokers receiving 1 mg estradiol experienced only half the increase compared to nonsmokers. In conclusion, thinness and smoking are important risk factors for osteoporosis development, but are counteracted by hormone replacement therapy.     

Effect of combined risedronate and hormone replacement therapies on bone mineral density in postmenopausal women

Both hormone replacement therapy (HRT) and bisphosphonates are efficacious in the prevention and treatment of postmenopausal osteoporosis. Combined therapy with bisphosphonate and HRT is likely to be used in clinical practice, and limited data are available regarding its efficacy and safety. This was a 1-yr, double blind, placebo-controlled study in which 524 postmenopausal women received daily treatment with conjugated equine estrogens (0.625 mg) alone or in combination with risedronate (5 mg). Women who had not undergone hysterectomy received medroxyprogesterone acetate (up to 5 mg, daily or cyclically) at the discretion of the investigator. The primary efficacy end point was the percent change from baseline in mean lumbar spine bone mineral density (BMD) at 1 yr. Changes in BMD at the proximal femur and forearm, bone turnover markers, and histology and histomorphometry were also assessed. At 12 months, significant (P < 0.05) increases from baseline in lumbar spine BMD were observed in both treatment groups (HRT-only, 4.6%; combined risedronate-HRT, 5.2%); the difference between the two groups was not statistically significant. Both therapies led to significant increases in BMD at 12 months at the femoral neck (1.8% and 2.7%, respectively), femoral trochanter (3.2% and 3.7%), distal radius (1.7% and 1.6%), and midshaft radius (0.4% and 0.7%). The differences between groups were statistically significant (P < 0.05) at the femoral neck and midshaft radius. Both combined risedronate-HRT and HRT-only produced significant decreases in the biochemical markers of bone turnover, with somewhat greater decreases in the combined treatment group. Bone biopsy data showed normal bone structure and normal mineralization with either treatment. Expected decreases in bone turnover were observed and were greater in the combined treatment group (68-79% reduction relative to baseline values, P < 0.005). Overall, combined treatment had a safety profile similar to that of HRT-only, including bone and gastrointestinal safety profiles. In conclusion, the combined treatment with risedronate and HRT had a favorable effect on BMD similar to that of HRT alone at the lumbar spine and slightly, but significantly, greater than that of HRT alone at the femoral neck and midshaft radius. The combined treatment was well tolerated, and there were no adverse effects on the skeleton.     

Alveolar and postcranial bone density in postmenopausal women receiving hormone/estrogen replacement therapy: a randomized,double-blind,placebo-controlled trial

BACKGROUND: We conducted a 3-year, double-blind, randomized, placebo-controlled study to determine whether the positive effects of hormone/estrogen replacement therapy (H/ERT) on postcranial bone density are accompanied by similar positive effects on oral bone mass. METHODS: A total of 135 postmenopausal women (aged 41-70 years) with no evidence of moderate or severe periodontal disease were randomized to receive daily oral conjugated estrogen (Premarin; 0.625 mg) alone or in combination with medroxyprogesterone acetate (Prempro; 0.625 and 2.5 mg, respectively) or placebo. All subjects received calcium carbonate (1000 mg/d) and cholecalciferol (400 [corrected] IU/d) supplements. The primary efficacy end points were the changes in alveolar crest height and alveolar bone density. Alveolar crest height was measured on bite-wing radiographs, and changes in alveolar bone mass were assessed by means of digital-subtraction radiography. Postcranial bone density was measured in the lumbar spine and left proximal femur by means of dual-energy x-ray absorptiometry. RESULTS: Hormone/estrogen replacement therapy significantly increased alveolar bone mass compared with placebo (+1.84% vs +0.95% [P =.04]), and tended to improve alveolar crest height (+4.83% vs +3.46% [P =.34]). Bone mineral density of the proximal femur significantly increased in the H/ERT compared with the placebo group (total proximal femur, +3.59% vs +0.22% [P =.001]; neck, +2.05% vs -0.34% [P =.02]; trochanter, +3.49% vs +0.08% [P<.001]), but not the lumbar spine (+1.01% vs +0.17% [P =.39]). Changes in alveolar bone mass correlated with bone density changes in the total femur (r = 0.28 [P =.02]) and femoral trochanter (r = 0.25 [P =.04]) in the H/ERT but not in the placebo group. CONCLUSIONS: Postcranial and oral bone mass were increased in postmenopausal women receiving H/ERT. Improvement in oral bone health constitutes an additional benefit of H/ERT.     

The effect of low dose nylestriol-levonorgestrel replacement therapy on bone mineral density in women with postmenopausal osteoporosis

OBJECTIVE: Recently our studies have shown that nylestriol in combination with levonorgestrel prevented bone loss, decreased bone turnover rate and increased the maximal loading of bone without obvious side effects in retinoic acid (RA) induced osteoporotic rats. In addition to the animal experiments, we evaluate the effect of Compound Nylestriol Tablet (CNT) on bone mineral density (BMD) in women with postmenopausal osteoporosis. Compound Nylestriol Tablet, which contains 0.5 mg of nylestriol (cyclopentylethinyl estriol) and 0.15 mg of levonorgestrel per tablet, was authorized as a new anti-osteoporotic agent for clinical trial in postmenopausal osteoporosis. METHODS: One year's clinical observation was performed in 191 eligible patients who were randomly divided into two groups (A and B). In group A, 119 patients were treated for one year with CNT (one tablet per week) and in group B, 72 patients with placebo. Bone mineral density of lumbar antero-posterior spine (L1-L4), lateral spine, total hip and total forearm positions including radius+ulna at the ultra distal areas, mid areas, and one-third areas, were measured before and after treatment. Biochemical parameters and effects of CNT on uterus, and breast were observed. RESULTS: We found that patients treated with CNT had a significant decrease of bone loss in total forearm, including radius+ulna at the ultra distal, mid, and 1/3 areas compared with control subjects (all P < 0.05). An improved BMD tendency could be seen at the lumbar spine. There were no differences in the observed biochemical variables. No side-effects on uterus, or mammary glands observed. None of the patients had uterine bleeding or vertebral fractures during one year's CNT treatment. CONCLUSION: These data suggested that CNT is effective, safe and convenient in treating postmenopausal osteoporosis.     

Prevention of femoral and lumbar bone loss with hormone replacement therapy and vitamin D3 in early postmenopausal women: a population-based 5-year randomized trial

The long term effects of hormone replacement therapy (HRT) and vitamin D3 (Vit D) on bone mineral density (BMD) were studied. A total of 464 nonosteoporotic early postmenopausal women from the Kuopio Osteoporosis Study (n = 13100) were randomized to four groups: 1) HRT (sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate, 2) Vit D3 (300 and 100 IU/day during the fifth year), 3) HRT and Vit D combined, and 4) placebo. Lumbar (L2-L4) and femoral neck BMD were determined by dual x-ray absorptiometry (DXA) at baseline and after 2.5 and 5 yr of treatment. Intention to treat analysis (n = 464) showed that after 5 yr, lumbar BMD remained unchanged in the HRT and HRT plus Vit D groups [+0.2% (P = 0.658) and +0.9% (P = 0.117), respectively], whereas lumbar BMD decreased by 4.6% in the Vit D group and by 4.5% in the placebo group (P < 0.001 in both). The loss of femoral neck BMD was less in the HRT (-1.4%; P = 0.005) and HRT plus Vit D (-1.3%; P = 0.003) groups than in the Vit D and placebo groups (-4.3%; P < 0.001 in both). Among those 370 women who complied with the 5-yr treatment, the effect was more pronounced: lumbar BMD had increased by 1.5% in the HRT (P = 0.009) and by 1.8% in the HRT plus Vit D group (P = 0.005), with a plateau after 2.5 yr, whereas lumbar BMD had decreased in both the Vit D and placebo groups (4.6% and 4.7%; P < 0.001, respectively). Femoral neck BMD decreased again less in the HRT (-0.4%) and HRT plus Vit D (-0.6%) groups than in the Vit D and placebo groups (-4.4% in both). This study confirms the positive long term effect of HRT on BMD also seen in intention to treat analysis. The data suggest that low dose vitamin D3 supplementation does not prevent bone loss in healthy, nonosteoporotic, early postmenopausal women, and it confers no benefit additional to that of HRT alone.     

绝经妇女激素替代治疗观点的历史演变

随着妇女平均寿命的延长 ,绝经后的问题日益受到全社会的广泛关注 ,旨在改善妇女生活质量的激素替代治疗(ＨＲＴ)所引发的问题也不断涌现 ,ＨＲＴ对绝经后妇女的生活质量究竟是否有总体益处已成为目前关注的焦点。 2 0 0 2年 7月 9日 ,美国国立卫生研究院 (ＮＩＨ)心脏、肺和血液研究所 (ＮＨＬＢＩ)宣布妇女健康初始行动 (ＷＨＩ)中雌激素加孕激素预防健康绝经后妇女的临床试验由于乳腺癌发病相对风险增加 2 6% ,且并无总体益处予以提前终止 ,这是一项按循证医学进行的重要研究结果 ,将对今后绝经后妇女ＨＲＴ产生重大影响。自从 1963年Ｗ…     

行激素补充疗法的绝经后妇女子宫内膜安全性监测

目的　探讨应用激素补充疗法(HRT)的绝经后妇女子宫内膜安全性的监测方法。　方法　对60例绝经后行HRT妇女进行血清雌二醇(E2)测定;阴道B超(TVS)监测子宫体积和子宫内膜厚度;对部分患者行子宫内膜的病理学检查和雌激素受体(ER)、孕激素受体(PR)半定量检测。　结果　应用HRT后,子宫内膜明显增厚,均值从2.8mm升至3.9mm(P＜0.05);E2显著上升,由(20.6±6.9)ng/L升至(33.8±11.7)ng/L（P＜0.01）;子宫内膜厚度与E2呈正相关关系(r=0.94,P＜0.01);20例送检内膜中,2例简单型增生过长,1例复杂型增生过长,余为萎缩型;ER(+)19例,ER(++)1例;PR均为(+)。　结论　根据临床表现,并结合血清E2和TVS检测子宫内膜厚度,可对子宫内膜安全性进行初步评估;当E2＞45ng/L,子宫内膜厚度≥5mm时,则需进一步行子宫内膜病理学检查和ER测定。     

激素替代治疗与绝经后妇女心血管疾病的关系

在绝经前,女性发生心血管疾病的危险性较低,然而,伴随着更年期的到来,女性心血管疾病的发病率明显升高,激素替代治疗随之成为临床上预防心血管疾病的热点话题.激素替代治疗在预防绝经妇女心血管疾病方面的研究.结果 并不一致,其预防效果在一定程度上取决于接受治疗者个体情况的差异.因此,激素替代治疗应当注意用药的时间、用药的个体化...     

The effect of rheumatoid arthritis and steroid therapy on bone density in postmenopausal women

Objective. To assess bone mineral density (BMD) in postmenopausal women with rheumatoid arthritis (RA) and the relative effects of disease activity, disability, and past and current use of corticosteroids. Methods. One hundred ninety-five postmenopausal patients with RA were compared with 597 postmenopausal control subjects. Bone density was measured at the lumbar spine and the proximal femur using dual x-ray absorptiometry. Patients were divided into 3 groups according to corticosteroid use, i.e., never users (61%), current users (21%), and ex-users (18%). Results. Compared with controls, the never users had no difference in BMD at the lumbar spine, but a 6.9% reduction at the femur (95% confidence interval [95% CI] 3.4–10.3%). In current users (mean daily prednisolone dosage 6.9 mg), BMD was reduced by 6.5% at the spine (95% CI 0–13.0%) and by 7.4% at the hip (95% CI 1.2–13.6%) compared with never users, after adjustment for age, weight, duration of menopause, and functional disability. Mean BMD was similar in the ex-user and never user groups. Results were confirmed in 54 patients who had whole-body BMD measurements. There were inverse correlations between BMD and Health Assessment Questionnaire scores (femoral BMD r = –0.23, P < 0.01; whole-body BMD r = –0.40, P < 0.01) and between BMD and cumulative steroid dose (femoral BMD r = –0.32, P < 0.01; whole-body BMD r = –0.72, P < 0.01). Conclusion. Osteoporosis in postmenopausal women with RA is more evident at the hip than the spine, and the most important determinants of bone loss are disability and cumulative corticosteroid dose. Low-dose steroids cannot be used with complacency, but recovery after discontinuation of use may be possible.     

Circulating estradiol and osteoprotegerin as determinants of bone turnover and bone density in postmenopausal women

Osteoprotegerin (OPG) is a recently identified cytokine that acts as a decoy receptor for the receptor activator of NF kappa B ligand. OPG has been shown to be an important inhibitor of osteoclast differentiation and activation in rodent models. Estrogen is known to suppress bone resorption, and the action of estrogen on bone may be mediated by OPG. The relationship between endogenous estrogen and circulating OPG levels and bone status in human populations is unclear. Thus, the aim of this study was to investigate the relationship between biochemical markers of bone turnover and bone density and circulating OPG and endogenous estradiol levels in a population-based cohort of postmenopausal women. Subjects were 180 women ages 55-91 yr (mean age, 67 yr). Serum estradiol was measured using an auto-analyzer. Serum concentrations of OPG were determined by ELISA. Markers of bone formation and resorption were measured by standard methods. Bone mineral density at total body, total hip, femoral neck, and lumbar spine was measured by dual energy x-ray absorptiometry. There was a significant inverse relationship between estradiol and all bone turnover markers (r-values from -0.46 to -0.23; P < 0.05). Serum estradiol was positively related to absolute bone density at all sites and to change in bone density at the hip and femoral neck by univariate analysis (r-values from 0.15-0.29; P < 0.05). We observed a weak inverse association between OPG and serum-based bone turnover markers (r-values -0.18 and -0.16; P < 0.05). There was a significant positive relationship between OPG and bone mineral density at total body, total hip, and femoral neck (r-values from 0.17-0.2; P < 0.05) by univariate analysis, which was lost after adjustment for age and body mass index. There was a significant weak positive relationship between circulating OPG and serum estradiol (r = 0.18; P < 0.02). We observed no significant relationships between OPG and bone turnover markers measured in urine. We conclude that the variation in circulating endogenous estradiol levels is an important factor contributing to levels of bone turnover and bone density at the menopause. Our observations also suggest that circulating levels of OPG may reflect OPG activity in bone and are related to circulating endogenous levels of estradiol. We have previously reported high levels of variability in urine markers of bone resorption, and we suggest that this could account for the absence of a significant association between these markers and circulating OPG.     

Use of hormone replacement therapy by postmenopausal women in the United States

BACKGROUND: The benefits and risks of hormone replacement therapy (HRT) in postmenopausal women are not fully defined, and individual characteristics and preferences may influence decisions to use this therapy. Previous studies of postmenopausal women who use HRT have been conducted in local or highly selected cohorts or have not focused on current use. OBJECTIVE: To examine sociodemographic, clinical, and psychological factors associated with current use of HRT in a national population-based cohort. DESIGN: Random-digit telephone survey. SETTING: Probability sample of U.S. households with a telephone. PARTICIPANTS: 495 postmenopausal women 50 to 74 years of age in 1995. MEASUREMENTS: Current use of HRT. RESULTS: Current use of HRT was reported by 37.6% of women (58.7% of those who underwent hysterectomy and 19.6% of those who did not undergo hysterectomy; P = 0.001). In multivariable analyses, use of HRT was more common among women in the South (adjusted odds ratio, 2.67 [95% CI, 1.08 to 6.59]) and West (odds ratio, 2.76 [CI, 1.01 to 7.53]) than the Northeast. Use was more common among college graduates (odds ratio, 3.72 [CI, 1.29 to 10.71]) and less common among women with diabetes mellitus (odds ratio, 0.17 [CI, 0.05 to 0.51]). Other cardiac risk factors and most psychological characteristics were not associated with HRT use. CONCLUSIONS: Sociodemographic factors, such as region and education, may be more strongly associated with use of HRT than clinical factors, such as risk for cardiovascular disease. Future efforts should focus on understanding sociodemographic variations, defining which women are most likely to benefit, and targeting therapy to them.     

Analysis of the contribution of dydrogesterone to bone turnover changes in postmenopausal women commencing hormone replacement therapy

Although gestagens have been reported to influence bone metabolism, whether these contribute to the beneficial effects of hormone replacement therapy (HRT) on the skeleton of postmenopausal women is currently unclear. To address this question, we compared changes in bone turnover markers after commencing HRT in 26 postmenopausal women randomized to receive 8 weeks of treatment with 2 mg estradiol daily or 2 mg estradiol plus 10 mg dydrogesterone daily. Serum and second morning void urine samples were obtained at baseline (twice) and after 1, 2, 4, and 8 weeks. Serum estradiol was measured by RIA, urinary total deoxypyridinoline (DPD) excretion by high pressure liquid chromatography, and serum osteocalcin and C-terminal procollagen peptide by enzyme-linked immunosorbent assay. The increase in serum estradiol after treatment with estradiol alone was slightly, but significantly, greater than that in the combination group (P = 0.04). Although estradiol suppressed urinary DPD excretion to a greater extent when given alone (P = 0.02), osteocalcin levels were significantly higher in this group than in women receiving combination therapy (P = 0.04). To assess the effect of dydrogesterone on the balance between formation and resorption in more detail, we subsequently compared the ratio between formation and resorption markers in the two treatment groups. We found that osteocalcin/DPD and C-terminal procollagen peptide/DPD ratios were significantly higher in women treated with estradiol alone (P < 0.0001 and P = 0.002, respectively), suggesting that dydrogesterone may reduce formation relative to resorption. These results suggest that gestagens may reduce estrogen's beneficial effects on the skeleton of postmenopausal women, as assessed over the first 8 weeks of replacement therapy.     

Effects of hormone replacement therapy on coagulation and fibrinolysis in postmenopausal women

It has been speculated that hormone replacement therapy (HRT) containing relatively low dose of estrogen would be different from oral contraceptive pills in causing thromboembolism because activation of coagulation depends on the amount of estrogen. In contrast to this knowledge, activation of coagulation pathways has been detected in postmenopausal women treated with HRT in the observational and clinical studies. In this regard, recent studies have reported a 2～4 fold risk of venous thromboembolism or pulmonary embolism in postmenopausal women receiving HRT than in non-users of estrogen. On the other hands, HRT has shown to enhance systemic fibrinolysis with decreased plasma plasminogen activator inhibitor-1 (PAI-1) levels. In addition, levels of D-dimer exhibited a significant inverse correlation with PAI-1 levels, suggesting enhanced fibrinolysis potential. However, small doses of estrogen/ progestogen induce increases in fibrinolytic capacity via a marked reduction of PAI-1. In other words, HRT at conventional dosages may affect fibrinolytic activity to a greater extent than coagulation activity, whereas the converse trend holds at higher estrogen doses. The increase in fibrinolytic potential was independent of any effect on coagulation of CEE at conventional dosages. However, in contrast to healthy postmenopausal women, we recently reported that HRT did not significantly decrease PAI-1 antigen levels and rather, increased tissue factor activity and prothrombin fragment F₁₊₂ levels from baseline in hypertensive and/or overweight postmenopausal women. Activation of coagulation following HRT may not be balanced by activation of fibrinolysis in some postmenopausal women. Thrombogenic events are considered more likely in patients with certain heritable conditions, such as platelet antigen-2 (PIA-2) polymorphisms. Further, Factor V Leiden mutation increases the risk of primary and recurrent venous thromboembolic events by three to sixfold and the risk of myocardial infarction. Indeed, HRT may decrease or increase atherothrombosis risk depending on the presence of Factor V Leiden mutation. Thus, HRT should not be initiated in women with established coronary artery disease or the coexistence of other risk factors for hypercoagulability-malignancy, immobility, obesity, diabetes, advanced age, or inherited traits. However, HRT at conventional dosages improves fibrinolysis potential in healthy postmenopausal women.     

Effects of hormone replacement therapy on coagulation and fibrinolysis in postmenopausal women

It has been speculated that hormone replacement therapy (HRT) containing relatively low dose of estrogen would be different from oral contraceptive pills in causing thromboembolism because activation of coagulation depends on the amount of estrogen. In contrast to this knowledge, activation of coagulation pathways has been detected in postmenopausal women treated with HRT in the observational and clinical studies. In this regard, recent studies have reported a 2 to approximately 4 fold risk of venous thromboembolism or pulmonary embolism in postmenopausal women receiving HRT than in non-users of estrogen. On the other hands, HRT has shown to enhance systemic fibrinolysis with decreased plasma plasminogen activator inhibitor-1 (PAI-1) levels. In addition, levels of D-dimer exhibited a significant inverse correlation with PAI-1 levels, suggesting enhanced fibrinolysis potential. However, small doses of estrogen/progestogen induce increases in fibrinolytic capacity via a marked reduction of PAI-1. In other words, HRT at conventional dosages may affect fibrinolytic activity to a greater extent than coagulation activity, whereas the converse trend holds at higher estrogen doses. The increase in fibrinolytic potential was independent of any effect on coagulation of CEE at conventional dosages. However, in contrast to healthy postmenopausal women, we recently reported that HRT did not significantly decrease PAI-1 antigen levels and rather, increased tissue factor activity and prothrombin fragment F(1+2) levels from baseline in hypertensive and/or overweight postmenopausal women. Activation of coagulation following HRT may not be balanced by activation of fibrinolysis in some postmenopausal women. Thrombogenic events are considered more likely in patients with certain heritable conditions, such as platelet antigen-2 (PIA-2) polymorphisms. Further, Factor V Leiden mutation increases the risk of primary and recurrent venous thromboembolic events by three to sixfold and the risk of myocardial infarction. Indeed, HRT may decrease or increase atherothrombosis risk depending on the presence of Factor V Leiden mutation. Thus, HRT should not be initiated in women with established coronary artery disease or the coexistence of other risk factors for hypercoagulability-malignancy, immobility, obesity, diabetes, advanced age, or inherited traits. However, HRT at conventional dosages improves fibrinolysis potential in healthy postmenopausal women.     

Combined hormone replacement therapy improves endothelial function in healthy postmenopausal women

OBJECTIVES: Large scale epidemiological studies suggest that hormone replacement therapy (HRT) reduces cardiovascular events in postmenopausal women. Improvement in endothelial function may contribute to this protective effect. DESIGN: In a prospective, double blind study, 61 healthy postmenopausal women were randomized to receive either oral continuous combined HRT [oestradiol 2 mg and norethisterone acetate (NETA) 1 mg per day] or placebo. Endothelial function, assessed by flow-mediated vasodilation (FMD) of the brachial artery and expression of soluble endothelial cell adhesion molecules (CAM) were determined before, after 3 and 6 months of therapy. RESULTS: The FMD was significantly improved in women on combined HRT (from 5.97% to 10.94% after 3 months and to 10.58% after 6 months; both P < 0.01 versus baseline values) and did not change in the placebo group (6.92% at baseline, 5.86% after 3 and 6.26% after 6 months). After 3 months of combined HRT, significant decreases of 24.6% for E-selectin and 13.9% for intercellular adhesion molecule-1 (ICAM-1) were observed (both P < 0.01 versus baseline values) and were sustained after 6 months of therapy, whilst no differences emerged in the placebo group. CONCLUSIONS: Oestradiol and norethisterone acetate improve endothelial function by both enhancing FMD and reducing the levels of soluble E-selectin and ICAM-1 in healthy postmenopausal women.     

Monofluorophosphate combined with hormone replacement therapy induces a synergistic effect on bone mass by dissociating bone formation and resorption in postmenopausal women: a randomized study.

Sodium fluoride stimulates bone formation and has been used to treat osteoporosis for decades despite debate about the antifracture efficacy. Hormone replacement therapy (HRT) results in only modest increases in bone mineral density (BMD). However, for women with low bone mass, the ideal therapy should not only inhibit bone resorption but simultaneously stimulate bone formation to increase bone mass above the fracture threshold. We thus performed a randomized, double-blind, placebo-controlled intervention study to prospectively investigate the effect of a low dose of fluoride, in combination with HRT, on BMD and biochemical markers of bone turnover. One hundred healthy postmenopausal women (60-70 yr old) were thus randomly assigned to: 1) HRT [transdermal 17beta-estradiol, releasing 50 microg/day; plus oral norethisterone acetate (NETA), 1 mg/day]; or 2) oral monofluorophosphate (MFP; equivalent to fluoride, 20 mg/day); or 3) HRT+MFP; or 4) placebo, for 96 weeks. All participants received a calcium supplement of 1000 mg/day. Sixty-eight women completed the study. We found a pronounced, linear increase in spinal BMD during treatment with HRT+MFP [11.8% (1.7% SEM)], which was significantly greater than the increase in the HRT group [4.0% (0.5% per yr); P < 0.05]. MFP produced a smaller increase [2.4% (0.6% per yr)], whereas there was no change in the placebo group [0.0% (0.5% SEM)]. Similar changes were found at the other skeletal sites (distal forearm, hip, and total body). Markers of bone formation showed a fall in the HRT group, which was significantly more pronounced than in the combined HRT+MFP group. A nonsignificant increase was found in the MFP group, whereas the placebo group showed a decrease caused by calcium treatment. The marker of bone resorption decreased significantly more in the HRT and the HRT+MFP groups than in the placebo group but tended to increase in the MFP group. In conclusion, this study shows, by use of biochemical markers of bone turnover, that bone resorption and formation may be dissociated, as a result of actions of two compounds with diverging effects on bone turnover. Furthermore, the synergistic effects of relatively low doses of the compounds suggested statistically and clinically significant increases in trabecular and probably also cortical bone. Adverse effects were relatively rare and mild.