Multisystem evaluations of the long-term effects of tibolone on postmenopausal monkeys

This long-term study (2 years) was designed to compare the effects of tibolone (LoTib at 0.05 mg/kg and HiTib at 0.2 mg/kg) with those of conjugated equine oestrogens (CEE) alone (0.042 mg/kg) and CEE continuously combined with medroxyprogesterone acetate (MPA) (0.167 mg/kg) on coronary artery atherosclerosis, bone, mammary gland and uterus in ovariectomised cynomolgus monkeys fed a moderately atherogenic diet. Despite reductions in plasma concentrations of high density lipoprotein cholesterol in tibolone-treated monkeys, there was no exacerbation of coronary artery atherosclerosis. Tibolone was equivalent to, or slightly better than, CEE and CEE + MPA in protecting against postmenopausal bone loss and loss of bone strength. Tibolone also resulted in less stimulation of breast and endometrial tissue compared with CEE and CEE + MPA. In conclusion, the results suggest that tibolone is a cardiovascular-safe treatment that is effective for the prevention of osteoporosis and that may have advantages over CEE or CEE + MPA with regard to endometrial and breast safety.     

Effects of raloxifene on bone density,biomarkers, and histomorphometric and biomechanical measures in ovariectomized cynomolgus monkeys

OBJECTIVE: The purpose of this study was to determine the effect of raloxifene on bone density, strength, metabolism, and histomorphometric characteristics in ovariectomized cynomolgus monkeys. DESIGN: A prospective, longitudinal study was designed to examine the effects of conjugated equine estrogens (0.04 mg/kg, CEE) and raloxifene (1 or 5 mg/kg, R1 and R5, respectively) on bone density, biomarkers, histomorphometry, and strength. Control groups included ovariectomized and sham-operated monkeys. Treatment was initiated the day after ovariectomy and continued for 24 months. Bone biomarker data were collected at baseline and every 3 months after surgery. Bone mass was determined at baseline and every 6 months after ovariectomy. Iliac biopsies were collected at baseline and 16 months postovariectomy, and the second lumbar vertebra and left midshaft femur collected at necropsy were examined histomorphometrically. Bone biomechanical properties were determined for the right femur and vertebrae. RESULTS: Compared with the placebo-treated ovariectomized monkeys, the high-dose raloxifene group had lower levels of alkaline phosphatase, tartrate-resistant acid phosphatase, urinary CrossLaps (collagen degradation products), and greater bone mass in the lumbar vertebrae. In the endocortical compartment, the high-dose raloxifene group had significantly lower mineralizing surface, mineral apposition rate, and bone formation rate in the iliac biopsy collected at 16 months and lower bone formation rate in the second lumbar vertebra. Within the midshaft femur, low-dose raloxifene significantly decreased the osteonal and total bone formation rates and also prevented the decrease in Young's modulus induced by ovariectomy in the midshaft femur. CONCLUSIONS: High-dose raloxifene prevented the development of osteopenia in the ovariectomized monkey by reducing bone turnover, albeit to a lesser extent than CEE. Histomorphometric and biomarker data suggest that mechanisms underlying the effect of raloxifene differ somewhat from that of CEE.     

Effects of lasofoxifene on bone in surgically postmenopausal cynomolgus monkeys

OBJECTIVE: The purpose of this study was to evaluate the effects on bone of two doses of the selective estrogen receptor modulator lasofoxifene in surgically postmenopausal cynomolgus monkeys for 24 months. The primary endpoint of this study was biomechanical testing of animals treated for 2 years. DESIGN: The design of the study was a five-group (sham-ovariectomy, ovariectomy, conjugated [0.02 mg/kg], and two doses of lasofoxifene [1.0 and 5.0 mg/kg]), parallel arm design, with the treatments lasting for 24 months. Bone biomarker and estradiol data were collected at baseline and 3, 6, 12, 18, and 24 months after surgery. Vertebral bone mineral density was determined at baseline and every 6 months after ovariectomy. Hip bone density was determined at baseline and 12 and 24 months postovariectomy. Iliac bone biopsies were collected at 7 months, and the second lumbar vertebra and left femur were collected at 24 months after initiation of treatment for histomorphometric examination. The third lumbar vertebra and right femur were tested for mechanical strength after 24 months of treatment. RESULTS: Lasofoxifene and conjugated estrogens prevented ovariectomy-induced increases in serum alkaline phosphatase and CrossLaps and resulted in increased vertebral (all three treatments) and hip (conjugated estrogens and high-dose lasofoxifene only) bone mineral density, although both doses of lasofoxifene exceeded the doses projected to be used in women. In the 7-month iliac biopsy specimens, both doses of lasofoxifene reduced bone turnover rates. These histomorphometric changes were not present in either the vertebral or femoral compartments measured after 24 months of treatment. Lasofoxifene-treated animals did not differ from ovariectomized controls in mechanical strength testing of either the third lumbar vertebra or right femur. CONCLUSIONS: Lasofoxifene prevented ovariectomy-induced increased bone turnover and loss of bone mineral density without having a detrimental effect on bone strength.     

A comparison of tibolone and hormone replacement therapy on coronary artery and myocardial function in ovariectomized atherosclerotic monkeys.

OBJECTIVE: Tibolone is used to prevent osteoporosis and to treat climacteric symptoms. The objectives of these studies were to measure and compare the effects of tibolone with hormone replacement therapy on coronary artery vascular reactivity and myocardial function and to relate these outcomes to treatment-induced plasma lipid/lipoprotein concentrations and atherosclerosis. DESIGN: One hundred forty-eight adult ovariectomized cynomolgus monkeys were fed an atherogenic diet for 24 months while receiving one of five oral treatments: no treatment (control, n = 31); conjugated equine estrogens (CEE), given at the equivalent of 0.625 mg/day ( n = 27); CEE (same dose) plus medroxyprogesterone acetate (MPA), given at the equivalent of 2.5 mg/day ( n = 29); low-dose tibolone (LoTib; 0.625 mg/day equivalent, n = 30); or high-dose tibolone (HiTib; 2.5 mg/day equivalent, n = 31). RESULTS: Quantitative coronary angiography showed that endothelium-mediated dilation was enhanced (17.5 +/- 5%, p = 0.002) in the CEE-treated group (but not other treatment groups) compared with the control. Both doses of tibolone and CEE reduced the incidence of dobutamine-induced ST-segment depression (LoTib: 33%, HiTib 25%, and CEE: 23%) compared to the control (79%) ( p = <0.05). Neither vascular reactivity nor dobutamine-induced myocardial ischemia were associated with treatment-induced changes in atherosclerosis or plasma lipid/lipoprotein concentrations. CONCLUSIONS: Tibolone, unlike CEE, has no benefit for endothelium-mediated dilation. Despite these differences, both tibolone and CEE reduced the incidence of myocardial ischemia, whereas CEE+MPA had no effect. It is speculated that tibolone may have direct effects on the myocardium that protect against myocardial ischemia.     

The effect of low-dose conjugated equine estrogens and cyclic MPA on bone density

OBJECTIVE: to compare the effect of 0.3 and 0.625 mg conjugated equine estrogens on bone mineral density (BMD) in a private practice setting. METHODS: postmenopausal women interested in hormone replacement therapy were prescribed either 0.3 or 0.625 mg conjugated equine estrogens daily with 10 mg medroxyprogesterone acetate days 1-12 of the month. All women were given calcium citrate 1000 mg/day and vitamin D 400 IU/day. DEXA bone mineral density studies of the spine and hip were performed at baseline and 1 year. RESULTS: there was no significant difference in BMD at the spine, the trochanter or the femoral neck compared with baseline in either the 0.625 or 0.3 mg group. The mean percent increase in BMD for the 0.3 versus 0.625 mg group was: spine 2.6 versus 3.8%, femoral neck 1.8 versus 1.5%, and trochanter 0.5 versus 2.6%. CONCLUSION: both the 0.625 mg dose and the 0.3 mg dose of conjugated equine estrogens preserved BMD at the spine and hip over one year in early postmenopausal women who were also given cyclic medroxyprogesterone acetate, calcium citrate and vitamin D.     

Effects of long-term hormone replacement and of tibolone on choline acetyltransferase and acetylcholinesterase activities in the brains of ovariectomized,cynomologus monkeys

We examined long-term effects of low and high doses of tibolone, conjugated equine estrogens, and conjugated equine estrogens plus medroxyprogesterone acetate on choline acetyltransferase and acetylcholinesterase activities within different regions of the brain in cynomologus monkeys. All treatments were administered for 2 years. None of the treatments produced significant increases in either choline acetyltransferase or acetylcholinesterase in any of eight brain regions analyzed. In contrast, treatment with conjugated equine estrogens plus medroxyprogesterone acetate, but not conjugated equine estrogens alone, produced significant reductions in both choline acetyltransferase and acetylcholinesterase in the medial septum/diagonal band of Broca compared with untreated controls. Treatment with tibolone also resulted in significant reductions in both choline acetyltransferase and acetylcholinesterase in the medial septum/diagonal band of Broca, and this effect was dose-related. These findings are the first to report the effects of long-term therapies used by postmenopausal women on cholinergic measures in the primate brain. The findings are consistent with recent reports in rats, and suggest that any positive effects of long-term estrogen or hormone replacement therapy on cognitive processes are probably not due to significant effects on choline acetyltransferase or acetylcholinesterase activities.     

Comparative effects of tibolone and conjugated equine estrogens with and without medroxyprogesterone acetate on the reproductive tract of female cynomolgus monkeys

OBJECTIVE: To measure the effects of 2 years' treatment with tibolone on the reproductive tract of female monkeys (Macaca fascicularis) in comparison with conventional hormone replacement therapy. DESIGN: Ovariectomized adult female monkeys were randomized for 2 years of treatment into five groups: controls (n = 31); tibolone at 0.05 mg/kg (LoTIB group; n = 30); tibolone at 0.2 mg/kg (HiTIB group; n = 31); conjugated equine estrogens (CEE) at 0.042 mg/kg (CEE group; n = 28); or CEE + medroxyprogesterone acetate (MPA) at 0.167 mg/kg (CEE + MPA group; n = 29). Endpoints included vaginal cytology; uterine weight; histopathologic evaluation of the uterus, vagina, and cervix; histomorphometry of the endometrium; and immunohistochemical detection of the proliferation marker Ki67 and progesterone receptor in endometrial tissue. RESULTS: Endometrial atrophy was found in 29 of 30 and 23 of 31 animals in the LoTIB and HiTIB groups, respectively, compared with 0 of 28 and 11 of 29 in the CEE and CEE + MPA groups, respectively. All ovariectomized control animals had atrophic endometria. No complex or atypical hyperplasia was seen. Simple endometrial hyperplasia of a significant degree was seen in 3 of 31 HiTIB-treated animals, 1 of 30 LoTIB-treated animals, 26 of 28 CEE-treated animals, and 16 of 29 CEE + MPA-treated animals, and in none of the control animals. Marked simple endometrial hyperplasia and Ki-67 expression was induced by CEE and partially antagonized by MPA. LoTIB and HiTIB slightly increased endometrial thickness, whereas CEE and CEE + MPA induced a marked increase of 350% and 200%, respectively. Neither LoTIB nor HiTIB increased endometrial proliferation (Ki67 labeling) or induced vaginal keratinization. Endometrial bleeding was not seen in tibolone-treated animals but was present in 10 of 29 animals given CEE + MPA. CONCLUSIONS: The effect of tibolone on the uterus and lower reproductive tract was minimal. The lack of a proliferative response of the endometrium to tibolone, coupled with the lower incidence of endometrial bleeding, suggests that tibolone may have advantages over CEE and CEE + MPA regarding endometrial safety and efficacy.     

A comparative study of two hormone replacement therapy regimens on safety and efficacy variables

Objective: To assess the effect of tibolone on endometrial safety, plasma estradiol concentrations, lipid metabolism and climacteric symptoms in comparison to sequential conjugated equine estrogens and medroxyprogesterone acetate in postmenopausal women. Methods: In a randomised, open-label, 6-cycle, group-comparative study, the effects on the aforementioned parameters were studied with tibolone 2.5 mg/day (N = 13) continuously, and with conjugated equine estrogens 0.625 mg/day continuously, combined with medroxyprogesterone acetate 5 mg/day (N = 11) (CEE/MPA) sequentially, during 12 days of each 28-day cycle. Within-group statistical analysis was performed with Student's t-test for paired samples, whereas between-group statistics were performed using the Student's t-test for independent groups. Results: Cytological evaluation revealed no endometrial stimulation in either group. In the tibolone group, there were no effects on estradiol levels, whereas in the CEE/MPA group, an increase in total and non-SHBG-bound estradiol plasma levels was reported. In the tibolone group, there were significant decreases in plasma total cholesterol, triglycerides, HDL-cholesterol and VLDL-cholesterol, whereas no significant changes in LDL-cholesterol and IDL-cholesterol were reported. In the CEE/MPA group there were significant decreases in plasma total cholesterol, HDL-cholesterol and LDL-cholesterol, whereas there were no significant changes in triglycerides, IDL-cholesterol and VLDL-cholesterol. Climacteric symptoms, particularly vasomotor episodes, decreased similarly in both groups. Conclusions: Both tibolone and CEE/MPA were safe with respect to effects on the endometrium and both treatments induced changes in the plasma profiles of certain lipid and lipoprotein parameters. However, the overall clinical implications of these changes are unknown. Finally, both regimens were equally effective in the treatment of climacteric symptoms     

Effects of tibolone and hormone replacement therapy on the breast of cynomolgus monkeys

OBJECTIVE: To measure the effects of 2 years of treatment with tibolone on the breasts of cynomolgus macaques (Macaca fascicularis) in comparison with conventional hormone replacement therapy. DESIGN: Ovariectomized cynomolgus macaques were randomized into five groups and treated for 2 years. Groups included controls (n = 31) and four drug treatments, including tibolone at 0.05 mg/kg (LoTIB, n = 30) or 0.2 mg/kg (HiTIB, n = 31), conjugated equine estrogens at 0.042 mg/kg (CEE, n = 28), or CEE + medroxyprogesterone acetate (MPA) at 0.167 mg/kg (CEE + MPA, n = 29). Endpoints included histologic, histomorphometric, and immunohistochemical assessment of the mammary gland. RESULTS: Tibolone did not cause stimulation of the breast in contrast to distinct proliferative responses of the breast to CEE and CEE + MPA, as measured by increases in breast epithelial tissue area and expression of the proliferation marker Ki67 in breast epithelial cells. Tibolone at the higher dose increased progesterone receptor expression in the breast relative to controls, indicating partial estrogen-agonist activity, but without induction of proliferation. Progesterone receptor expression was also induced by CEE. CONCLUSIONS: Tibolone may have an advantage over conventional hormone replacement therapy because it does not stimulate proliferation in the breast. This lack of mammotrophic effect may reflect a lower risk for promotion of breast cancer.     

Effects of tibolone on estrogen biosynthesis in the mammary tissue of postmenopausal monkeys

OBJECTIVE: To evaluate the long-term effects of tibolone on estrone sulfate (E1S)-sulfatase activity in breast tissue in a primate model (Macaca fascicularis) in comparison with conventional hormone therapies. DESIGN: Ovariectomized female animals (n = 112) were randomized into five groups and treated for 2 years. Treatment included tibolone at 0.05 mg/kg (LoTib, n = 23) or 0.2 mg/kg (HiTib, n = 23), conjugated equine estrogens at 0.042 mg/kg (CEE, n = 24), CEE + medroxyprogesterone acetate at 0.167 mg/kg (CEE+MPA, n = 21), or placebo (controls, n = 21). E1S-sulfatase activity was evaluated by incubating homogenized breast tissue with [H]-E1S. Thin-layer chromatography was performed to separate the products estrone (E1) and estradiol (E2). Histomorphometry was performed to measure the amount of epithelial and fat tissue in the mammary gland. RESULTS: Significantly more E2 than E1 was produced in all groups. E1S-sulfatase activity did not differ among the groups. E1S-sulfatase activity was highest in HiTib animals with less fatty breasts (5.9 fmol total estrogen/mg of protein/min; P < or =0.05) and lowest in HiTib animals with more fatty breasts (2.8 fmol total estrogen/mg of protein/min; P = 0.004 relative to less fatty breasts). CONCLUSIONS: We conclude that tibolone had a differential effect on local estrogen biosynthesis in animals with high and low breast fat content. Therefore, breast tissue composition affects the steroidogenic response to hormonal treatment.     

Postmenopausal hormone therapy and mammographic breast density

OBJECTIVE: The aim of this study was to evaluate the effects of different types of hormone replacement therapy (HRT) on mammographic density. MATERIALS AND METHODS: In a prospective 1-year study, 103 postmenopausal women were randomized to receive tibolone 2.5 mg/die, continuous conjugated equine estrogens 0.625 mg/die plus medroxyprogesterone acetate (MPA) 5mg/die or placebo. Mammograms were performed at baseline and after 12 months of treatment. Mammographic density was quantified according to the Wolfe classification. RESULTS: After 12 months of HRT 16 of the 35 patients (45.1%) receiving continuous combined hormonal therapy showed an increase of breast density change in the Wolfe classification. After treatment with tibolone, an up grading in breast density, according to Wolfe's classification, was found in 2 of the 43 patients (2.3%). No changes were recorded in the 25 patients of the control group. The difference between the group treated with continuous combined hormonal therapy and the control group was highly significant (p<0.001). The difference in breast density between patients in treatment with tibolone and the control group was not statistically significant (p=0.34). DISCUSSION: Continuous combination HRT may be more commonly associated with an increase of mammography density than tibolone treatment.     

A 5-year study on the effect of hormone therapy, tibolone and raloxifene on vaginal bleeding and endometrial thickness

OBJECTIVES: To study the effect of standard and low-dose estrogen-progestin therapy (EPT), tibolone and raloxifene on the incidence of vaginal spotting/bleeding and endometrial thickness over a 5-year period. METHODS: Seven hundred eighty-six postmenopausal women were studied in an open prospective design. Vaginal spotting/bleeding and endometrial thickness as assessed by transvaginal ultrasonography was compared between six categories of women over a 5-year period: three categories in women on continuous combined estrogen-progestin therapy, one category under tibolone, one category under raloxifene and one under no treatment. More specifically, women received tibolone 2.5 mg (N = 204), raloxifene HCl 60 mg (N = 137), conjugated equine estrogens 0.625 mg/medroxyprogesterone acetate 5mg (N = 122), 17beta-estradiol 2mg/norethisterone acetate 1mg (N = 58), 17beta-estradiol 1mg/norethisterone acetate 0.5mg (N = 76) or no therapy (controls, N = 189). Women with suspected endometrial pathology were referred for hysteroscopy. RESULTS: Bleeding/spotting incidence was highest among standard dose EPT users (conjugated equine estrogens 0.625 mg/medroxyprogesterone acetate 5mg: 40.1%, 17beta-estradiol 2mg/norethisterone acetate 1mg: 44.8%, p < 0.001 compared to controls). Low-dose EPT associated with lower incidence of spotting/bleeding (34.1%). The incidence under tibolone and raloxifene was 22.5% and 2.9%, respectively, while 3.2% of women not receiving therapy reported vaginal spotting/bleeding. Mean endometrial thickness was not significantly affected in any of the groups studied. The drop-out rate due to spotting/bleeding was higher in the two higher dose EPT regimens. After logistic regression analysis, age at baseline was the only significant predictor of subsequent spotting/bleeding (b = -0.25, S.E. = 0.09, p = 0.006), while menopausal age and pre-treatment serum FSH had marginal significance. CONCLUSIONS: EPT, tibolone and raloxifene do not appear to associate with significant changes in endometrial thickness in the majority of cases. The low-dose EPT regimen associated with a decreased incidence of unscheduled spotting/bleeding compared to the standard dose regimens. Tibolone expressed a favorable endometrial profile, as seen in its effect on unscheduled spotting/bleeding and mean endometrial thickness. Raloxifene associated with the lowest incidence in S/B and the lowest drop-out rate.s.     

Effect of tibolone compared with sequential hormone replacement therapy on carbohydrate metabolism in postmenopausal women

OBJECTIVE: To investigate the effects of tibolone on carbohydrate metabolism, and to compare these effects with those of a sequential regimen of conjugated equine estrogens and medrogestone. METHODS: This was an open-label, multicentre, comparative study. Seventy-two postmenopausal women were randomized to receive either tibolone 2.5 mg/day or conjugated equine estrogens 0.6 mg plus sequential medrogestone 5 mg (CEE/M) for six 28-day cycles. Carbohydrate metabolism was evaluated at baseline and after three and six cycles of treatment by an oral glucose tolerance test (OGTT). A blood sample was taken at 30, 60, 90 and 120 mm after glucose 75 mg dosing for determination of plasma glucose, insulin and connecting peptide (C-peptide) levels. RESULTS: The changes from baseline of glucose, insulin and C-peptide area-under-the-curve (AUC) values were not statistically significant after 3 and 6 months of tibolone or CEE/M treatment. There was a small transitory decrease in HbA(1C) after three cycles of treatment with tibolone. CONCLUSION: The effects of tibolone and CEE/M on carbohydrate metabolism were considered to have no clinical significance.     

Effects of two continuous hormone therapy regimens on C-reactive protein and homocysteine

OBJECTIVE: To compare the effects of two continuous hormone therapy (HT) regimens on the cardiovascular risk markers, C-reactive protein (CRP) and homocysteine. DESIGN: A prospective study in which 43 postmenopausal women were randomly assigned to either tibolone 2.5 mg/day (n = 20) or 0.625 mg/day conjugated equine estrogens (CEE) plus continuous medroxyprogesterone acetate (MPA) 5 mg/day (n = 23). Serum levels of CRP, homocysteine, vitamin B12, and folate were determined before and during 12 weeks of therapy. RESULTS: C-reactive protein levels were increased by tibolone (76%; P < 0.001) and CEE+MPA (81%; P < 0.001). Neither tibolone nor CEE+MPA had any significant effect on homocysteine levels, but there was a significant difference between the effects of treatment over time (P = 0.046). Both tibolone and CEE+MPA reduced vitamin B12 levels (11%; P < 0.001, and 8%; P < 0.01, respectively), but had no statistically significant effect on folate levels. Individual changes in homocysteine levels were negatively associated with changes in vitamin B12 levels (r = -0.68; P < 0.01) after tibolone therapy. CONCLUSION: Both tibolone and CEE plus MPA increased CRP levels and reduced levels of vitamin B12. Neither therapy had any significant effect on homocysteine levels. Further long-term studies into the effect of HRT on these markers, and the relationship to cardiovascular disease risk, are required.     

Tibolone, oral or transdermal hormone replacement and colour Doppler analysis: a prospective, randomised pilot study

Objective: To compare the plasma thromboxane, the plasma viscosity and the Doppler flow modifications induced by tibolone and by oral or transdermal continuous combined hormone replacement therapy. Methods: Forty-two post-menopausal patients underwent either on: oral daily treatment with tibolone (2.5 mg) (Group I; n=14); or continuous oral administration of 0.625 mg conjugated equine estrogens + medroxyprogesterone 5 mg per day (Group II; n=14); or continuous estradiol transdermal supplementation, at a dose of 50 μg per day, + medroxyprogesterone 5 mg per day (Group III; n=14). The duration of the study was 6 months and the patients were submitted to transvaginal ultrasonographic evaluation of pelvic organs; Doppler analysis of the uterine, internal carotid and ophthalmic arteries; thromboxane and plasma viscosity assays in basal condition, and at 1, 3 and 6 months from the beginning of the study. Results: Although the endometrial thickness increased significantly, there were no cases in which it exceeded the normal range (≤5 mm). In all the three groups, the pulsatility index of the uterine, internal carotid and ophthalmic arteries significantly decreased during the therapy showing a reduced impedance since the first month of treatment. Similar variations were observed for the peak systolic blood flow velocity of the internal carotid and ophthalmic arteries. Hormone replacement therapy and tibolone induced a deep, significant and rapid decrease in plasma thromboxane and plasma viscosity levels. Conclusions: Hormone replacement therapy and tibolone seem to have beneficial effects on vascular and hemorrheological parameters.     

The effect of conjugated equine estrogens on ovariectomy-induced osteopenia in the rat

The effect of estrogen replacement on ovariectomy-induced bone loss was evaluated in mature Sprague-Dawley rats. Undecalcified tibia of ovariectomized rats were processed for quantitative histologic assessment of cancellous bone in longitudinal sections from the primary and secondary spongiosa of the proximal metaphysis. Bone content in tissue specimens was quantified as the parameter B. Ar, two-dimensional bone mineral area. Estrogen, supplied as orally administered conjugated equine estrogens, prevented bone loss through 6 weeks of treatment. The effect of conjugated equine estrogens was dose-dependent, with significant protection against bone loss observed at doses of 10 g/kg/day and higher.     

Postmenopausal femur bone loss: effects of a low dose hormone replacement therapy

OBJECTIVES: Previous studies indicate that low-dose hormone replacement therapy (LD-HRT) can relieve vasomotor symptoms and prevent spine bone loss. METHODS: In the present study, we evaluated the effects of a low dose of conjugated equine estrogens (CEE; 0.3 mg) associated with different progestins in continuous combined scheme [2.5 mg of medroxyprogesterone acetate (n=25), 5 mg dydrogesterone (n=27), 2.5 mg nomegestrol (n=11)] as single group, on femur bone mineral density (BMD) and bone metabolism in young postmenopausal women (相似文献   

Raloxifene reduces procarboxypeptidase U, an antifibrinolytic marker. A 2-year randomized, placebo-controlled study in healthy early postmenopausal women

OBJECTIVE: The aim of this study was to compare the long-term effects of two dosages of raloxifene with oral hormone therapy (HT; conjugated equine estrogens combined with medroxyprogesterone acetate) on procarboxypeptidase U. DESIGN: In a randomized, double-blind, placebo-controlled, 2-year study, 95 healthy, nonhysterectomized, early postmenopausal women received either daily raloxifene 60 mg (n = 24), raloxifene 150 mg (n = 23), HT (conjugated equine estrogens 0.625 mg + medroxyprogesterone acetate 2.5 mg, n = 24), or placebo (n = 24). At baseline and after 6, 12, and 24 months, fasting plasma procarboxypeptidase U concentrations were measured. RESULTS: Six months of treatment with raloxifene 60 mg and raloxifene 150 mg were associated with significant decreases in plasma procarboxypeptidase U concentrations, which were sustained after 12 and 24 months. Raloxifene 60 mg: t = 0, 619 +/- 89 U/L (mean +/- SD); t = 6, 574 +/- 87 U/L; t = 12, 571 +/- 96 U/L; t = 24, 568 +/- 92 U/L; ANCOVA versus placebo, P = 0.026. Raloxifene 150 mg: t = 0, 608 +/- 67 U/L; t = 6, 580 +/- 73 U/L; t = 12, 578 +/- 70 U/L; t = 24, 562 +/- 61 U/L; ANCOVA versus placebo, P = 0.039. No significant changes were found in the HT group. CONCLUSION: Long-term treatment with raloxifene reduced procarboxypeptidase U plasma concentrations.     

Two-year prospective and comparative study on the effects of tibolone on lipid pattern, behavior of apolipoproteins AI and B.

OBJECTIVE: To investigate long-term lipid and lipoprotein changes in postmenopausal women treated with tibolone in a prospective study using appropriate control groups. DESIGN: Seventy-six of 105 postmenopausal women initially selected for this study completed the 2-year follow-up. Patients were allocated into three groups. The first received 2.5 mg/day tibolone continuously (n = 27; group T), the second received 0.625 mg/day conjugated equine estrogen plus 2.5 mg/day of medroxyprogesterone (group E-P) continuously (n = 25), and a third group contained an additional 24 women who did not receive replacement therapy; these constituted the untreated control group (group C). Plasma lipids and lipoproteins were determined in all patients before joining the study and also at 12 and 24 months after being included. RESULTS: Women treated with tibolone experienced the greatest decreases in cholesterol, both total and high density lipoprotein (HDL), and triglycerides (TG), whereas the highest increase in HDL was observed in the group E-P. A decrease in low density lipoprotein levels was detected in both therapy groups, whereas a significant increase was observed in the control group. TG were increased after E-P therapy. In all the groups, apolipoprotein AI showed parallel trends to HDL and apolipoprotein B to low density lipoprotein. CONCLUSIONS: Both therapy groups, tibolone and E-P, induced changes in levels of plasma lipids, lipoproteins and apolipoproteins. Long-term tibolone treatment is associated with a marked and significant decrease in HDL apolipoprotein AI and TG, an effect that defines the major difference with standard HRT. Clearly, further studies are necessary to establish the definite risk/benefit ratio of tibolone with respect to its overall effect on lipid metabolism.     

Effects of tibolone and conventional hormone replacement therapies on arterial and hepatic cholesterol accumulation and on circulating endothelin-1, vascular cell adhesion molecule-1, and E-selectin in surgically menopausal monkeys

OBJECTIVE: Menopause and aging are associated with a marked increase in the incidence of coronary heart disease as well as reductions in circulating estrogen, progestogen, and androgen levels. The synthetic compound tibolone and its metabolites have estrogenic, progestogenic, and androgenic characteristics. In the present study, we compared the effects of tibolone, estrogen replacement therapy, and estrogen plus progestogen replacement therapy on arterial and hepatic lipid accumulation and on circulating soluble adhesion molecule and endothelin-1 concentrations in surgically postmenopausal cynomolgus monkeys. DESIGN: Animals were fed an atherogenic diet for 2 years while receiving either no hormone treatment (control, n = 31) or the following treatments at doses designed to mimic the human dose on a daily caloric intake basis: tibolone at 2.5 mg/day (HiTib, n = 31), tibolone at 0.625 mg/day (LoTib, n = 29), conjugated equine estrogens (CEE) alone at 0.625 mg/day (CEE, n = 29), or CEE plus continuous medroxyprogesterone acetate (MPA) at 2.5 mg MPA/day (CEE + MPA, n = 30). RESULTS: Relative to the control group, iliac artery total cholesterol content was not different in the HiTib, LoTib, and CEE + MPA groups but was significantly lower in the group receiving CEE only (P < 0.05). In contrast, hepatic free cholesterol content was reduced in all treatment groups [HiTib (P < 0.01), LoTib (P < 0.05), CEE (P < 0.01), and CEE + MPA (P < 0.05)], whereas hepatic total and esterified cholesterol content were reduced in the HiTib, CEE, and CEE + MPA groups (all P < 0.05). HiTib and CEE groups had lower hepatic triglyceride levels per milligram of protein (P < 0.05). Iliac arterial cholesterol content was highly correlated with hepatic cholesterol content and with previously published histomorphometrically determined coronary artery atherosclerosis, supporting the use of the iliac artery as a surrogate for the coronary artery in the monkey. Circulating levels of soluble vascular cell adhesion molecule-1 were significantly reduced in the HiTib (P < 0.02) and CEE (P < 0.05) groups, whereas soluble E-selectin was reduced in the CEE group only (P < 0.01). Plasma endothelin-1 was significantly reduced in the LoTib (P < 0.05), CEE (P < 0.01), and CEE + MPA (P < 0.01) groups. CONCLUSIONS: These results suggest that while tibolone caused marked depression of high-density lipoprotein cholesterol and a resultant twofold increase in the total plasma cholesterol/high-density lipoprotein cholesterol ratio, those effects did not result in exacerbation of iliac artery atherosclerosis, perhaps because of beneficial effects on vascular biology or hepatic metabolism.