Prevention of postmenopausal bone loss with exchange for short-term HRT for 1alpha-hydroxycholecalciferol

OBJECTIVE: The present study investigated bone turnover with exchange of hormone replacement therapy (HRT) by treatment with 1alpha-hydroxycholecalciferol in early postmenopausal women. METHODS: Subjects included a total of 75 postmenopausal women between 49 and 59 years of age who visited the Department of Obstetrics and Gynecology at Osaka Medical College Hospital for regular gynecological checkups and menopausal disorder, postmenopausal osteoporosis or hyperlipidemia, and were diagnosed with menopausal disorder or osteopenia. Changes in bone turnover and vertebral bone mineral density (BMD) in 28 patients who had undergone HRT; conjugated equine estrogen 0.625 mg daily and medroxyprogesterone acetate 2.5 mg daily) for at least 2 years and then switched to 1alpha-hydroxycholecalciferol (0.5 microg orally twice daily) and in 26 patients who were observed without drug administration after discontinuation of HRT were compared with those in 37 patients who continued HRT. BMD of the lumbar spine (L2-4) was determined using Dual Energy X-ray Absorptiometry. RESULTS: While we observed a significant decrease in vertebral bone mass in the HRT-no medication group at 12 months (P=0.049) and 18 months (P=0.013), there was no significant decrease in vertebral bone mass in either the continuous HRT group or the group with change of HRT to 1alpha-hydroxycholecalciferol. In the group with change of HRT to 1alpha-hydroxycholecalciferol, although urinary pyridinoline level increased significantly from the baseline level throughout the study period (P<0.05), serum propeptide of type-1 procollagen (P1CP) level also increased significantly from the baseline level throughout this period (P<0.001). Furthermore, significant increase from the baseline value (P<0.01) was observed in serum osteocalcin level at 6, 12 and 18 months. CONCLUSIONS: These results indicate that switching to 1alpha-hydroxycholecalciferol therapy after short-term HRT increased both bone resorption and bone formation, and permitted maintenance of increase in bone mass due to HRT for at least 18 months, though this switching accelerated bone turnover. This may have occurred because stimulation of bone formation induced by HRT was maintained by 1alpha-hydroxycholecalciferol, though bone turnover was slightly promoted because of withdrawal of HRT. This method was thus found to be very effective in preventing bone loss in patients who have discontinued HRT and are considered relatively contraindicated for use of estrogen.     

Ultra low-dose hormone replacement therapy and bone protection in postmenopausal women

OBJECTIVES: The aim of the present study was to evaluate the effects of low doses of hormone replacement therapy (HRT) in normal young postmenopausal women. METHODS: In an open trial healthy, non-obese postmenopausal women received for 2 years a low-dose continuous combined HRT (LD-HRT) containing 1mg estradiol+0.5 mg norethisterone acetate each pill for 28 days, or 0.5 mg of 17beta-estradiol and 0.25 mg of norethisterone acetate (Ultra low dose, Ultra-LD-HRT) along with 1000 mg of calcium per day. Control group consisted of women receiving only 1000 mg of calcium per day, for 2 years. Menopausal symptoms were evaluated by the Green climacteric scale for the first 12 weeks of the study while bleeding profiles, bone mineral density (BMD) and bone turnover were assessed for 24 months. RESULTS: LD-HRT and Ultra-LD-HRT were effective in reducing menopausal clinical symptoms. In the control group, BMD significantly (P<0.05) decreased at the spine (-2.8+/-0.2%), and femoral neck (-2.8+/-0.7%). In LD-HRT treated group BMD showed a significant (P<0.05) increase at the spine (5.2+/-0.7%), and femoral neck (2.8+/-0.4%) after 24 months. In the Ultra-LD-HRT treated women spine and femoral neck BMD showed a significant (P<0.05) increase (2.0+/-0.3 and 1.8+/-0.3%, respectively) after 24 months. In these women treated with LD-HRT and Ultra-LD-HRT the BMD values were significantly (P<0.05) different from those measured in calcium-treated women. CONCLUSIONS: LD-HRT and Ultra-LD-HRT can alleviate subjective symptoms providing an effective protection against the postmenopausal decrease of BMD.     

Prevention of postmenopausal bone loss by low and conventional doses of calcitriol or conjugated equine estrogen

OBJECTIVES: Estrogen deficiency is the most common cause of postmenopausal osteoporosis and estrogen replacement is well known to retard postmenopausal bone loss. Calcium supplement alone is generally considered to be insufficient for the prevention of bone loss associated with estrogen deficiency while the role of calcitriol is unclear. In the present study we examined the efficacy different doses of estrogen or calcitriol in the prevention of postmenopausal bone loss in Thais. METHODS: The subjects consisted of 146 Thai women no more than 6 years postmenopausal. The subjects were randomly allocated to receive 750 mg supplemental calcium alone, calcium and conjugated equine estrogen (CEE) at 0.3 or 0.625 mg, calcium and calcitriol at 0.25 or 0.5 microg daily. Those receiving CEE also took 5 mg medrogestone for 12 days each month. BMD at L2-4 and femoral neck were measured at baseline 1 year and 2 years after treatments. Data were expressed as mean +/- S.E. RESULTS: Subjects on supplemental calcium alone had approximately 2.5% decreases in L2-4 (P < 0.05) and femoral BMD (P < 0.01) at 2 years. CEE (0.3 mg) resulted in 3.20 +/- 1.2% increase in vertebral BMD (P < 0.05) while no significant change in BMD was demonstrated at the femoral neck. Likewise, 0.625 mg of CEE induced 5.4 +/- 1.4% increase in vertebral BMD at 2 years (P < 0.001) without change in the femoral BMD. In regard to calcitriol, no significant change in vertebral or femoral BMD was demonstrated with either 0.25 or 0.5 microg calcitriol. CONCLUSION: We concluded that calcitriol is effective in the prevention of early postmenopausal bone loss in Thais. It represents an option for the prevention of osteoporosis in postmenopausal women who are contraindicated for estrogen replacement.     

A prospective,randomized, placebo-controlled study of the dose effect of oral estradiol on bone mineral density in postmenopausal Chinese women

OBJECTIVES: One of the long-term consequences of estrogen deficiency in postmenopausal women is an increased risk of osteoporosis. Fractures of the hip and lumbar spine are associated with considerable morbidity and mortality. Estrogen replacement therapy reduces the risk of osteoporosis, but there is no clear agreement on the most appropriate doses to be used. The aim of this study was to compare changes in bone mineral density (BMD) measurements using conventional and lower dose estradiol. METHODS: A prospective, randomized, placebo-controlled 12-month study of the effect of 1 and 2 mg estradiol on BMD in 152 hysterectomized postmenopausal Chinese women with no contraindication to the use of estrogen replacement therapy. RESULTS: Over 12 months, spinal BMD in placebo treated patients decreased by a mean of 2% from baseline (-0.02+/-0.03 g/cm(2)) while it increased by 2% in the 1 mg (0.02+/-0.03 g/cm(2)) and 3% in the 2 mg group (0.03+/-0.03 g/cm(2)). Mean changes in BMD over 12 months in the hip were -0.02+/-0.02 g/cm(2) (-2%), 0.01+/-0.02 g/cm(2) (+1%) and 0.01+/-0.03 g/cm(2) (+1%) in the placebo, 1 and 2 mg estradiol groups, respectively (P<0.05). Relative to placebo, increases in BMD in both 1 and 2 mg groups were statistically significant for both spine and hip (P<0.05). However, there was no significant difference in the increase in BMD between the 1 and 2 mg doses for either lumbar spine or hip (P=0.82, 0.53, respectively). CONCLUSION: The results of our study show that a 1 mg dose of oral estradiol is effective in preventing bone loss in postmenopausal Chinese women.     

Does apolipoprotein E genotype relate to BMD and bone markers in postmenopausal women?

OBJECTIVES: Bone mineral density (BMD) and development of osteoporosis are partly determined by genetic factors. The associations between one of suggested candidate, apolipoprotein E (apo E) genotype to bone mineral density (BMD) and bone biochemical markers was studied in 464 subjects recruited from a population-based group of early postmenopausal women (n = 13100). Additionally, the influence of apo E genotype on BMD changes during a 5-year follow-up with or without hormone replacement therapy (HRT) was investigated. METHODS: Participants were randomized into two treatment groups: HRT group: Sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate with or without vitamin D3, 100-300 IU/day + calcium lactate, 500 mg/day (n = 232), and the non-HRT group: Calcium lactate, 500 mg/day alone or in combination with vitamin D3, 100-300 IU/day (n = 232). BMD was measured from the lumbar spine and proximal femur at baseline and after 5 years of treatment (n = 352). In a subgroup (n = 59), the serum concentrations of bone biochemical markers (intact osteocalcin (OC), bone-specific alkaline phosphatase (BAP) and type I collagen carboxy-terminal telopeptide (ICTP)) were measured at baseline and after 1 year of follow-up. RESULTS: At baseline, the BMDs were similar between the five apo E genotype groups (2/3, 2/4, 3/3, 3/4, 4/4). No significant differences in lumbar or femoral neck BMDs of women with the apo E4 allele were found compared with those without it. There was a statistically significant difference in 5-year BMD changes between the HRT and non-HRT groups. After 5 years, the BMD of the femoral neck had remained constant and the mean lumbar spine BMD had increased by 1.5% in the HRT group, whereas both BMDs had decreased by 4-5% in the non-HRT group. However, the apo E genotype did not modify the changes in BMD in either group. Additionally, the baseline concentrations of bone metabolic markers and their 1-year changes showed no genotype-related associations. CONCLUSIONS: The results of our population-based study indicate that apo E genotype does not modify lumbar or femoral neck BMDs or serum bone biochemical markers or their response to HRT in early postmenopausal Caucasian women.     

Effects of alendronate and hormone replacement therapy, alone or in combination, on bone mass in postmenopausal women with osteoporosis: a prospective, randomized study

The effectiveness of hormone replacement therapy (HRT) and alendronate, alone and in combination, was evaluated in 120 postmenopausal patients with osteoporosis with bone mineral density (BMD) measurements at least 2 SD below the mean value for young premenopausal subjects. They had no contra-indications to HRT or alendronate use and were randomized to three different treatment groups. Group I was treated with micronized 17 beta-oestradiol 2 mg and norethisterone acetate 1 mg/day per os, group II received alendronate 10 mg/day per os and group III received micronized 17 beta-oestradiol 2 mg, norethisterone acetate 1 mg/day per os and alendronate 10 mg/day per os for 1 year. Elementary calcium 1500 mg/day was supplied to patients in all three groups. Spinal and femoral neck BMD and markers of bone mineral metabolism were measured on each patient before treatment and 6 and 12 months after treatment in 95 patients. At the end of the 12th month, significant increases in spinal and femoral neck BMD were found in all groups. Increases in spinal BMD were significantly higher in patients treated with alendronate and alendronate with HRT when compared with patients treated with HRT only. No significant difference was found in femoral neck BMD changes between the groups. Significant decreases in bone resorption and markers of bone formation were observed in all groups. Alendronate was found to be more effective than HRT and could have a very beneficial effect when added to the HRT regimen in patients with postmenopausal osteoporosis. Alendronate might also be used in postmenopausal patients with osteoporosis when HRT is contra-indicated or when there is reluctance to use hormonal treatment.     

Effect of low-dose transdermal E2/NETA on the reduction of postmenopausal bone loss in women

OBJECTIVE: To assess the efficacy of a continuous-combined transdermal patch (estradiol/ norethisterone acetate [E(2)/NETA] 25/125; Estragest TTS, Novartis, Basel, Switzerland) in the reduction of bone loss in postmenopausal women. DESIGN: In a 96-week, double-blind, randomized, multicenter, parallel study, 124 healthy women with an intact uterus more than 4 years after menopause received either transdermal continuous-combined E(2)/NETA (0.025/0.125 mg/day) or placebo patch for 24 treatment cycles; diet was normalized for calcium intake. Lumbar spine bone mineral density (BMD) ranged from 0.969 to 0.805 g/cm2 with a mean annual BMD decrement ranging from 3% to 8% within the last 24 months. BMD at lumbar spine L(2)-L(4) (postero-anterior) and femur were assessed by dual energy x-ray absorptiometry after 6, 12, and 24 cycles. Efficacy variables included measurement of biochemical markers of bone turnover (3, 6, 12, and 24 months). RESULTS: BMD at lumbar spine was significantly higher at all time points in the E(2)/NETA group than in the placebo group (P < 0.0001). Significant increases in BMD (P < 0.0008) from baseline were observed at all sites after 24 months in the E(2)/NETA group compared with placebo, which demonstrated a decrease from baseline. At endpoint, statistically significant decrements in the values of bone remodeling markers were observed (P < 0.05) with E(2)/NETA. CONCLUSIONS: E(2)/NETA 25/125 Estragest TTS was more effective than placebo in reducing the activation frequency of bone remodeling and in preventing bone loss at the spine and hip. Effects on the hip were similar to those observed for higher doses of estrogen.     

Nitric oxide in postmenopausal women taking three different HRT regimens

OBJECTIVE: To search and compare the effects of three different HRT regimens on nitric oxide levels of postmenopausal women. METHODS: Four groups of postmenopausal women were included in this prospective, randomised, placebo controlled study. 34 women used 0.625 mg conjugated estrogen continuously combined with 5 mg medroxyprogesterone acetate, 32 women used 2.5 mg tibolone, 26 women used 50 mcg transdermal estrogen alone continuously and 32 women used placebo for 12 months. Before the treatment and after 1 year, serum NO (nitrate/nitrite) and some other biochemical parameters were evaluated. RESULTS: All HRT using groups had increased serum nitric oxide levels significantly compared to placebo group and also there was not any difference among three HRT using groups concerning to increases in nitric oxide levels. CONCLUSION: Both conjugated estrogen combined with continuous progestin and transdermal estrogen alone and also tibolone increases serum nitric oxide levels of postmenopausal women equally for 12-months of treatment.     

Peripheral quantitative computed tomography (pQCT) is useful for monitoring bone mineral density of the patients who receive hormone replacement therapy

OBJECTIVE: A forearm fracture (Colles' fracture) is often the first sign of osteoporosis and should alert the patient and physician to the possibility of underlying skeletal fragility. Therefore, the establishment of a more accurate and reliable method for the measurement of bone mineral density (BMD) at the distal radius would be beneficial for the patients who suffer from osteoporosis. The objective of the present study was to evaluate the usefulness of peripheral quantitative computed tomography (pQCT) to assess the change of BMD at the distal radius in early postmenopausal women who receive hormone replacement therapy (HRT). METHODS: Twenty healthy early postmenopausal women who were diagnosed as osteoporosis or osteopenia were randomized to either HRT or placebo treatment. We analyzed BMD of the distal radius by pQCT, lumbar spine by dual-energy X-ray absorptiometry (DXA) and the biochemical markers of bone turn over (osteocalcin, deoxypyridinoline) every 6 months. RESULTS: The placebo group showed a significant decrease from the baseline in the trabecular BMD of the radius at 12 months (7.4+/-2.5%) (p<0.05), whereas the HRT group showed a slight increase (0.7+/-2.2%). The changes in the trabecular BMD of the radius between the HRT and placebo groups were statistically different at 12 months (p<0.05). On the other hand, in the cortical BMD of the radius, no significant differences were seen between the changes of bone densities in the HRT and control groups after 1 year of treatment. pQCT could detect a significant loss of BMD of the radius in early postmenopausal women after 1 year and HRT prevented its loss. CONCLUSION: Our preliminary clinical trial showed that pQCT might be useful for the early detection of bone loss in early postmenopausal women and for the monitoring BMD of the patients who receive HRT.     

Once-weekly alendronate 70 mg and raloxifene 60 mg daily in the treatment of postmenopausal osteoporosis

OBJECTIVE: To compare the efficacy and tolerability of once-weekly (OW) alendronate (ALN) 70 mg and raloxifene (RLX) 60 mg daily in the treatment of postmenopausal osteoporosis. DESIGN: This 12-month, randomized, double-blind study enrolled 456 postmenopausal women with osteoporosis (223 ALN, 233 RLX) at 52 sites in the United States. Efficacy measurements included lumbar spine (LS), total hip, and trochanter bone mineral density (BMD) at 6 and 12 months, biochemical markers of bone turnover, and percent of women who maintained or gained BMD in response to treatment. The primary endpoint was percent change from baseline in LS BMD at 12 months. Adverse experiences were recorded to assess treatment safety and tolerability. RESULTS: Over 12 months, OW ALN produced a significantly greater increase in LS BMD (4.4%, P < 0.001) than RLX (1.9%). The percentage of women with > or = 0% increase in LS BMD (ALN, 94%; RLX, 75%; P < 0.001) and > or =3% increase in LS BMD (ALN, 66%; RLX, 38%; P < 0.001) were significantly greater with ALN than RLX. Total hip and trochanter BMD increases were also significantly greater (P < or =0.001) with ALN. Greater (P < 0.001) reductions in N-telopeptide of type I collagen and bone-specific alkaline phosphatase were achieved with ALN compared with RLX at 6 and 12 months. No significant differences in the incidence of upper gastrointestinal or vasomotor adverse experiences were seen. CONCLUSION: ALN 70 mg OW produced significantly greater increases in spine and hip BMD and greater reductions in markers of bone turnover than RLX over 12 months. A greater percentage of women maintained or gained BMD on ALN than RLX. Both medications had similar safety and tolerability profiles.     

The efficacy of two dosages of a continuous combined hormone replacement regimen

OBJECTIVES: To evaluate the efficacy of a low-dose combination of estradiol (E2) and norethisterone acetate (NETA) on bone markers, lipid and bleeding profiles and menopausal symptoms. METHOD: Ninety-six healthy Chinese postmenopausal women were allocated randomly to receive 1 mg E2/0.5 mg NETA (low-dose hormone replacement therapy (HRT)) or 2 mg E2/1 mg NETA (high-dose HRT) for 6 months. RESULTS: Bone resorption markers (collagen I N-terminal telopeptides (NTX) and deoxypyridinoline (dPyr)) were significantly reduced; -66 and -32%, respectively, in high-dose HRT versus -55 and -24%, respectively, in low-dose HRT. Bone-specific alkaline phosphatase remained unchanged with either combination of hormones. Total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) levels were decreased significantly (-12 and -13%, respectively, in high-dose HRT vs. -7 and -8% in low-dose HRT). High density lipoprotein cholesterol (HDL-C) was decreased to a lesser extent in low-dose HRT and triglycerides (TG) levels remained unchanged. Both the low and high-dose HRT were effective in alleviating menopausal symptoms. After 6 months of treatment, 2% of women in the low-dose HRT were bleeding compared with 23% in the high-dose HRT. Breast pain occurred in 2% of women in low-dose HRT compared with 15% in high-dose HRT. The endometrium in the majority of the women remained normal. CONCLUSION: Menopausal symptoms were reduced effectively in postmenopausal women on either low-dose or high-dose HRT. TC, LDL-C levels and bone resorption markers were reduced in a dose-dependent manner. Low-dose HRT provided a better bleeding profile and the incidence of breast pain was low.     

Efficacy of a soy rich diet in preventing postmenopausal osteoporosis: the Menfis randomized trial

Objectives: To compare the effect of a soy rich diet and hormone replacement therapy (HRT) on the main biomarkers of bone turnover and bone mineral density (BMD) at postmenopausal age. Methods: 187 healthy asymptomatic postmenopausal women, aged 39–60, were recruited and randomized into a soy rich diet group, a HRT group, and a control group. Bone biomarkers and BMD were evaluated at baseline and after 6 months at the end of the study. Results: Diet is not as effective as HRT in reducing the postmenopausal turnover; however diet stimulates bone osteoblastic activity, as evidenced by significant increase in osteocalcin concentrations. BMD decreases significantly only in the control group, but not in the intervention groups. Conclusions: Our data suggest that soy products could be effective in reducing the risk of osteoporosis in asymptomatic postmenopausal women, but our findings should be confirmed before recommending the diet as a valid alternative to HRT.     

Tofupill/Femarelle (DT56a): a new phyto-selective estrogen receptor modulator-like substance for the treatment of postmenopausal bone loss

OBJECTIVE: To evaluate the efficacy of Tofupill/Femarelle (DT56a), a novel phyto-selective estrogen receptor modulator (SERM), in preserving bone mineral density (BMD) in postmenopausal women. DESIGN: The study sample consisted of 98 healthy, postmenopausal women who were randomly allocated, on a double-blind basis, to receive either 644 mg/d DT56a (study group) or 344 mg/d DT56a supplemented with calcium (low-dose group) for 12 months. Each participant was assessed with a comprehensive health questionnaire, a detailed physical, and laboratory and pelvic sonogram examinations at entry and every 3 months thereafter. BMD was assessed by dual-energy x-ray absorptiometry (Lunar) of the lumbar spine and femoral neck before the study began and after 12 months of treatment. RESULTS: After 12 months of treatment, BMD had increased in the study group by 3.6% in the lumbar spine (P = 0.039) and by 2.0% in the femoral neck (NS). In the low-dose group, BMD had decreased in the lumbar spine by 0.6% (NS) and by 0.6% in the femoral neck (NS). Comparison of the change in bone density between the groups yielded a significant difference for the lumbar spine (P = 0.037). Neither group showed a change in endometrial thickness and sex hormone levels nor reported any side effects of treatment. CONCLUSIONS: Tofupill treatment in postmenopausal women increases BMD without unwanted estrogenic effect. Tofupill appears to be a promising phyto-SERM for the prevention of postmenopausal osteoporosis.     

Endometrial response to raloxifene compared with placebo, cyclical hormone replacement therapy, and unopposed estrogen in postmenopausal women.

OBJECTIVE: To determine the endometrial effects of raloxifene 60 mg/day in postmenopausal women as assessed by vaginal bleeding and endometrial thickness. DESIGN: Data from 1157 postmenopausal women were analyzed from a database consisting of four independent, double-blind, randomized, placebo-controlled trials (range = 6-30 months duration), a 24-month open-label randomized, cyclical hormone replacement therapy (HRT)-controlled trial, and a 6-month double-blind, randomized, unopposed estrogen-controlled trial. Vaginal bleeding rate was derived from self-reported adverse events collected at least every 6 months. Endometrial thickness was measured by ultrasonography at regular intervals. RESULTS: Raloxifene 60 mg/day was not significantly different from placebo with regard to the incidence of vaginal bleeding, the baseline-to-endpoint change in endometrial thickness, or the proportion of women experiencing an increase in endometrial thickness above baseline after either 12 or 24 months of therapy. Unexpected bleeding was reported significantly more frequently in the unopposed estrogen groups compared with the raloxifene group (raloxifene 60 mg/day, 0% versus estrogen, 50%; p = 0.002). A significantly greater baseline-to-endpoint increase in endometrial thickness was observed in both the HRT and estrogen groups compared with their respective raloxifene comparison group (raloxifene 60 mg/day, 0.01 +/- 2.0 mm versus HRT, 1.8 +/- 3.2; p < 0.001; raloxifene 60 mg/day, 1.1 +/- 1.7 mm versus estrogen, 7.8 +/- 3.8; p < 0.001). No cases of endometrial hyperplasia or cancer were diagnosed in the placebo or raloxifene 60 mg/day groups. Endometrial hyperplasia was diagnosed in one case in the HRT group and in two cases in the estrogen group. CONCLUSION: Raloxifene 60 mg/day for up to 30 months is not associated with vaginal bleeding or increased endometrial thickness in postmenopausal women.     

Fracture risk and bone density of peri- and early postmenopausal women with uterine leiomyomas

OBJECTIVES: Fracture risk and bone mineral density (BMD) among peri- and early postmenopausal women with leiomyomas requiring hysterectomy was evaluated. METHODS: We counted fractures among women with or without leiomyomas using data from the Kuopio Osteoporosis Study. The study population consisted of 6086 women aged 47-56 years with never-use of hormone replacement therapy (HRT) responding to the baseline and 5-year follow-up inquiries. Part of the sample (n=1271) underwent bone densitometry. RESULTS: Hysterectomy was carried out in 927 women, and 59% reported that this was attributable to leiomyomas. The hazard ratio (HR) was 0.68 (95% CI 0.49-0.94) for any and 0.73 (95% CI 0.43-1.26) for distal forearm fracture among women with leiomyomas compared to those without any. Among women postmenopausal at baseline, the corresponding HRs were 0.62 (95% CI 0.44-0.87) and 0.54 (95% CI 0.31-0.96); after adjusting for age, time since menopause weight, height and previous fracture 0.69 (95% CI 0.49-0.97) and 0.63 (95% CI 0.35-1.11). The baseline BMDs were 1.15 g/cm2 among hysterectomized leiomyoma and 1.12 g/cm2 (ns) among non-hysterectomized women at lumbar (L2-L4), and 0.94 and 0.93 g/cm2 (ns) at femoral sites. The follow-up lumbar BMDs were 1.13 and 1.09 g/cm2 (p<0.001) and the corresponding femoral values were 0.90 and 0.89 g/cm2 (ns), respectively. Among postmenopausal women, the corresponding baseline lumbar BMDs were 1.15 and 1.08 g/cm2 (p<0.001), femoral 0.93 and 0.90 g/cm2 (p=0.003); the follow-up lumbar BMDs 1.13 g/cm2 versus 1.07 g/cm2 (p<0.001); femoral BMDs 0.89 versus 0.87 (ns). CONCLUSIONS: Peri- and early postmenopausal women with a history of leiomyomas seem to have better BMD and less fractures compared with those without leiomyomas. This may be mediated through higher estrogen levels leading to higher BMD and the growth of leiomyomas.     

Differential effects of oral conjugated equine estrogen and transdermal estrogen on atherosclerotic vascular disease risk markers and endothelial function in healthy postmenopausal women

BACKGROUND: Recent studies have revealed that HRT may increase the risk for atherosclerotic vascular disease (ASVD). METHODS: We investigated the effects of HRT via different administration routes on the markers for ASVD and endothelial function in healthy postmenopausal women. The oral HRT group (n=18) received conjugated equine estrogen 0.625 mg/day; the transdermal HRT group (n=18) received 17beta-estradiol (E2) gel 0.6 mg/day for 6 months. The control group (n=30) had no treatment for 6 months. RESULTS: The C-reactive protein (CRP) rose from 0.129+/-0.116 to 0.752+/-0.794 mg/dl (P<0.01) in the oral HRT group but remained unchanged in the transdermal HRT and control groups. The flow-mediated vasodilation (FMD) in the brachial artery was increased significantly by HRT from 6.0% before oral HRT to 14.7% after oral HRT (P<0.001) and from 5.9% before transdermal HRT to 13.9% after transdermal HRT (P=0.001). CONCLUSIONS: These data suggest that oral estrogen induces ASVD risk by increasing acute inflammation; however, transdermal estrogen avoids this untoward effect. Additionally, transdermal estrogen exerts a positive effect on endothelial function similar to that of oral estrogen. Therefore, the transdermal route might be favourable in terms of ASVD risks.     

Prevention of postmenopausal bone loss with minimal uterine bleeding using low dose continuous estrogen/progestin therapy: a 2-year prospective study

Objective: To re-examine the minimal effective dose of conjugated estrogen (CEE)-progestin hormone replacement on postmenopausal bone loss. Design: A 2-year, prospective, open label, randomized study. Setting: Department of Obstetrics and Gynecology of a university hospital. Participants: Fifty-two postmenopausal or oophorectomized women. Intervention: One of the following regimens was continuously administered for 2 years: (1) CEE 0.625 mg/day, (2) CEE 0.625 mg + medroxyprogesterone (MPA) 2.5 mg/day, (3) CEE 0.31 mg + MPA 2.5 mg/day and (4) control. Measurements: Lumbar spine and femoral BMD by dual energy X-ray absorptiometry (DXA), a monthly based incidence of bleeding, serum lipids, PTH, calcitonin, Al-p, and osteocalcin. Results: Of the 52 patients enrolled in this study, 49 patients completed the 1 year of therapy and 36 completed the 2- year study. The control group showed a significant decrease in lumbar BMD over the 2 years (P < 0.05). The % changes in lumbar BMD at 2 years of CEE alone, CEE 0.625 + MPA and CEE 0.31 + MPA were 8.52% (95% confidence intervals; 4.61 ∼ 12.4%), 7.4% (0.60 ∼ 14.2%) and 3.20% (0.61 ∼ 5.84%), respectively, and were significantly higher than pretreatment values. The incidence of bleeding was significantly lower in women taking CEE 0.31 mg + MPA. HDL cholesterol increased in women taking CEE 0.625 mg alone or with MPA. No significant changes in lipid profiles were seen in the control or in the group of women taking CEE 0.31 mg + MPA. Conclusions: Continuous hormone replacement therapy (HRT) using 0.31 mg of CEE and 2.5 mg of MPA is effective in increasing lumbar BMD in postmenopausal or oophorectomized women and can be an appropriate option for women with a normal lipid profile or those women wishing to eliminate unscheduled bleeding.     

The effect of low dose hormone therapy on mammographic breast density

OBJECTIVES: To evaluate the effect of two standard and one low dose continuous hormone therapy regimens on mammography. METHODS: One hundred and thirty-two non-hysterectomized postmenopausal women were randomly allocated either to conjugated equine estrogens 0.625 mg plus medroxyprogesterone acetate 5 mg (CEE/MPA, n=38), 17beta-estradiol 2 mg plus norethisterone acetate 1 mg (E2/NETA, n=44) or 17beta-estradiol 1 mg plus norethisterone acetate 0.5 mg (low E2/NETA, n=50). Treatment was continuous and the study period lasted 12 months. Main outcome measures were the changes according to Wolfe classification between baseline and 12-month mammograms. RESULTS: Five (13.2%) women in the CEE/MPA group showed an increase in breast density. Fourteen (31.8%) women on E2/NETA and 6 (12.2%) on low E2/NETA treatment revealed an increase in breast density. No woman exhibited an involution of fibroglandular tissue. CONCLUSIONS: Different hormone therapy regimens have a variable impact on breast density probably depending on the steroid used. Low dose hormone therapy associates with significantly lesser increase in breast density.     

Adverse endometrial effects during long cycle hormone replacement therapy

Objectives: treatment with unopposed estrogen is known to increase the risk of endometrial hyperplasia, atypia, and carcinoma, and therefore the administration of a progestin during hormone replacement therapy (HRT) is recommended. The addition of a progestestin may cause unwanted side effects. Progestin administration of various durations are therefore used in HRT. Study design: data were obtained about endometrial histopathology, bleeding interval and compliance in 240 early postmenopausal women receiving HRT with a progestin administered for 10 days during 12 week or 4 week cycles of estrogen administration. These regimens were studied for as long as 4 years. The daily estrogen given was 17β-estradiol 2 mg per day which was reduced to 1 mg day during the last 6 days of each cycle. The progestin used was norethindrone acetate, given at a dose of 1 mg per day. Results: the incidence of endometrial hyperplastic changes, i.e. simple or complex hyperplasia, atypia or cancer, was significantly higher in the 12 weeks cycle than in the monthly cycle group (P=0.003), with an overall annual incidence of 5.6% in the 12 weeks cycle group and 1% in the monthly cycle group. One case of atypical hyperplasia and one case of endometrial adenocarcinoma was observed in the long cycle group. Long cycle treatment produced more irregular bleeding pattern. Accordingly, the rate of drop-out due to bleeding was significantly higher in the long cycle group (P<0.01). Conclusion: we conclude that the long cycle HRT modality investigated did not improve compliance and may increase the risk of endometrial hyperplasia and eventually cancer compared to conventional HRT with a monthly cycle. Caution using long cycle HRT regimens is advisable, and careful monitoring of the endometrium during treatment is recommended.     

The effect of tibolone on bone mineral density in postmenopausal women with osteopenia or osteoporosis--8 years follow-up

OBJECTIVES: This longitudinal observational study evaluated the effect of 8 years of uninterrupted treatment of tibolone on bone mineral density (BMD) in postmenopausal women with significant osteopenia or osteoporosis. MATERIAL AND METHODS: Subjects were 66 postmenopausal women (29 with moderate or severe osteopenia and 37 with osteoporosis) who took tibolone (2.5 mg nocte) uninterruptedly for over 8 years and who attended for annual BMD assessments. Their mean age was 66.7 (0.86) years (range 50-86 years). BMD measurements at the lumbar spine and proximal femur were performed annually by dual-energy X-ray absorptiometry (DEXA). RESULTS: During the 8 years of treatment with tibolone there was a significant increase in BMD at the spine (P < 0.001) and at the hip (P < 0.001). Women who did not have previous oestrogen therapy had significantly greater response to tibolone than those who had previous treatment with conventional hormone replacement therapy (HRT). CONCLUSION: This long-term observational study provides evidence of the effectiveness of tibolone in postmenopausal women with moderate/severe osteopenia and osteoporosis in terms of a significant increase in BMD.