The cardiovascular effects of selective estrogen receptor modulators.

Coronary artery disease (CAD) is the main contributor of mortality among postmenopausal women. Menopause-associated estrogen deficiency has both metabolic and vascular consequences that increase the risk for CAD. Hormone therapy (HT) has been reported to have a beneficial effect on metabolic and vascular factors influencing the incidence of CAD. Although observational studies have reported that HT reduces significantly the risk for CAD, randomized clinical trials (WHI, HERS, ERA) have questioned the efficacy of HT in primary and secondary CAD prevention despite confirming the lipid-lowering effect of HT. In the aftermath of the WHI, increased interest has been given to the action of selective estrogen receptor modulators (SERMs) and their effect on the cardiovascular system. The chemical structure of SERMs, either triphenylethilyn (tamoxifen) or benzothiophene (raloxifene) derivatives, differs from that of estrogens. SERMs are nonsteroidal molecules that bind, with high affinity, to the ER. SERMs induce conformational changes to the ligand-binding domain of the ER that modulate the ability of the ER to interact with coregulator proteins. The relative balance of coregulators within a cell determines the transcriptional activity of the receptor-ligand complex. SERMs therefore may express an estrogen-agonist or estrogen-antagonist effect depending on the tissue targeted. SERMs express variable effects on the metabolic and vascular factors influencing the incidence of CAD. SERMs have been reported to modulate favorably the lipid-lipoprotein profile. Toremifene expresses the most beneficial effect followed by tamoxifene and raloxifene, while ospexifene and HMR-3339 have the least effect and may even increase triglycerides. Raloxifene and tamoxifene decrease serum homocysteine levels and C-reactive proteins (CRP), which are both markers of CAD risk. Raloxifene has been reported to increase the nitric oxide (NO)-endothelin (ET)-1 ratio and, thus, contribute to proper endothelial function and vasodilation. Toremifene has no effect on the NO-ET-1 ratio. Finally, raloxifene decreases the vascular cell adhesion molecules and the inflammatory cytokines TNF-alpha and IL-6. Of the SERMs, raloxifene has had the most extensive evaluation regarding the effect on the vascular wall of endothelium. Although not confirmed by large clinical trials, raloxifene has been reported to have an effect on the cohesion of the intercellular junction (VE-cadherin) and the synthesis-degradation of extracellular matrix (MMP-2). The Multiple Outcomes Raloxifene Evaluation (MORE) study has reported that raloxifene may have a cardioprotective effect when administered to postmenopausal women at high risk for CAD disease.

Circulating levels of atherogenesis-associated adipocytokines and apoptotic markers are differentially influenced by hormone therapy, tibolone and raloxifene in healthy postmenopausal women.

OBJECTIVE: Estrogen agonist compounds may exert cardioprotective activity by modulating adipocytokine concentration and apoptosis. The objective of this study was to evaluate the effects of hormone therapy, tibolone and raloxifene on the serum adipocytokines resistin and adiponectin as well as on circulating markers of receptor-mediated apoptosis. Design Randomized, open-label, intervention study in the Menopause Clinic of a University Hospital. METHODS: One hundred healthy postmenopausal women were randomized to the following groups: conjugated equine estrogens 0.625 mg (CEE) (n = 16); 17 beta-estradiol 1 mg plus norethisterone acetate 0.5 mg (E(2)/NETA) (n = 15); tibolone 2.5 mg (n = 18); raloxifene HCl 60 mg (n = 20); and no treatment (n = 19). Eighty-eight women completed the 3-month study period. Main outcome measures were levels of serum adiponectin, resistin, soluble Fas and Fas ligand. RESULTS: Levels of serum adiponectin decreased significantly in the tibolone group (baseline: 10 556.7 +/- 4213.5 ng/ml; 3 months: 7856.3 +/- 3450.7 ng/ml; p = 0.0001) and increased in the CEE group (baseline: 9268.1 +/- 5158 ng/ml; 3 months: 11 302.6 +/- 4980.9 ng/ml; p = 0.01). Serum resistin values increased only in the tibolone group (baseline: 2.81 +/- 0.89 ng/ml; 3 months: 3.55 +/- 1.31 ng/ml; p = 0.04), while the level of Fas ligand decreased significantly in the E2/NETA (baseline: 70.4 +/- 21.9 pg/ml; 3 months: 62.1 +/- 18.6 pg/ml; p = 0.02) and tibolone group (baseline: 68.2 +/- 25.7 pg/ml; 3 months: 59.2 +/- 21.7 pg/ml; p = 0.01). CONCLUSIONS: Of the regimens investigated, only unopposed estrogens may exert an atheroprotective effect through the increase of adiponectin and a resultant favorable lipid and anti-inflammatory profile.

Patient compliance with alendronate, risedronate and raloxifene for the treatment of osteoporosis in postmenopausal women.

OBJECTIVES: The aim was to investigate patient compliance with different osteoporosis medications commonly prescribed in clinical practice, to determine risk factors associated with discontinuation and to evaluate quality of life changes. RESEARCH DESIGN AND METHODS: We conducted a 1-year observational study of patients of age > or = 60 years in a clinical setting at 917 sites in 10 European countries (Germany, Greece, UK, Sweden, Netherlands, Romania, Norway, Finland, Denmark, Estonia), Lebanon and South Africa. Demographic data, concomitant diseases, the reasons for intervention, educational, socio-economical status and disease knowledge were captured at baseline. Self-reported compliance, discontinuation data and health status were collected. MAIN OUTCOME MEASURES: Out of 5198 patients, 3490 (67.1%) patients received 60 mg daily raloxifene (RAL), 452 (8.7%) 10 mg daily alendronate (AQD), 769 (14.8%) 70 mg once weekly alendronate (AQW) and 487 (9.4%) 5 mg daily risedronate (RIS). Among patients completing the study (4231, 81%), the percentage of patients with high compliance was 80% (RAL), 79% (AQD), 65% (AQW) and 76% (RIS). The discontinuation due to side effects was highest on AQW (7.0%), followed by AQD (6.4%), RAL (3.8%) and RIS (3.4%). The discontinuation-rate was higher for patients with a history of surgical menopause, increased age, lack of knowledge about medical prevention of osteoporosis and thin frame as a reason for intervention. The EQ-5D weighted index showed the highest improvement for RIS (0.13), followed by RAL (0.11), AQD (0.08) and AQW (0.07). CONCLUSIONS: Data from this non-interventional observational study indicate moderate overall compliance and discontinuation rate with the prescribed osteoporosis medications.

The differential effect of estrogen, estrogen-progestin and tibolone on coagulation inhibitors in postmenopausal women.

OBJECTIVES: Hormone therapy increases the risk of venous thromboembolism, possibly through a negative effect on coagulation inhibitors. The aim of the study was to assess the effect of conjugated equine estrogens alone or in combination with medroxyprogesterone acetate, low-dose 17beta-estradiol combined with norethisterone acetate and tibolone on inhibitors of coagulation. METHODS: Two hundred and sixteen postmenopausal women received orally either conjugated equine estrogens 0.625 mg (CEE, n=24) or tibolone 2.5 mg (n=24) or CEE+medroxyprogesterone acetate 5 mg (CEE/MPA, n=34) or 17beta-estradiol 1 mg+norethisterone acetate 0.5 mg (E2/NETA, n=66) or no therapy (control, n=68) for 12 months. Plasma antithrombin, protein C and total protein S were measured at baseline and at 12 months. RESULTS: CEE, CEE/MPA and E2/NETA treatment were associated with a significant decrease in antithrombin levels (CEE: baseline 235.6+/-47.6 mg/l, follow-up 221.3+/-48.3 mg/l, p=0.0001; CEE/MPA: baseline 251.1+/-38.6 mg/l, follow-up 225.0+/-42.6 mg/l, p=0.009; E2/NETA: baseline 257.1+/-59.4 mg/l, follow-up 227.1+/-50.4 mg/l, p=0.007; tibolone: baseline 252.6+/-62.4 mg/l, follow-up 261.9+/-59.1 mg/l, p=0.39). Protein C decreased significantly in the CEE and CEE/MPA groups (CEE: baseline 3.64+/-1.17 mg/l, follow-up 2.48+/-1.47 mg/l, p=0.004; CEE/MPA: baseline 3.24+/-1.23 mg/l, follow-up 2.61+/-1.38 mg/l, p=0.001; E2/NETA: baseline 3.24+/-1.10 mg/l, follow-up, 3.15+/-1.11 mg/l, p=0.08; tibolone: baseline 3.26+/-1.25 mg/l, follow-up 3.09+/-1.32 mg/l, p=0.37). Protein S decreased significantly only in the CEE/MPA group (CEE: baseline 19.4+/-2.76 mg/l, follow-up 18.0+/-2.45 mg/l, p=0.56; CEE/MPA: baseline 18.4+/-3.42 mg/l, follow-up 14.5+/-3.43 mg/l, p=0.005; E2/NETA: baseline 19.0+/-3.11 mg/l, follow-up 19.5+/-3.43 mg/l, p=0.18; tibolone: baseline 18.5+/-3.09 mg/l, follow-up 18.0+/-4.09 mg/l, p=0.32). CONCLUSIONS: Estrogen and estrogen-progestin therapy are associated with a reduction in coagulation inhibitors, the extent of which depends on the regimen administered. Tibolone appears to have no effect on inhibitors of coagulation.

Effect of hormone replacement therapy, tibolone and raloxifene on serum lipids, apolipoprotein A1, apolipoprotein B and lipoprotein(a) in Greek postmenopausal women.

The aim of this study was to assess the effect of estrogen, two regimens of continuous combined hormone replacement therapy (HRT), tibolone and raloxffene on serum lipid, apolipoprotein A1 and B and lipoprotein(a) levels in Greek postmenopausal women. A total of 350 postmenopausal women were studied in a prospective open design. Women were assigned to one of the following regimens depending on the presence of risk factors for osteoporosis, dimacteric symptoms and an intact uterus: conjugated equine estrogen 0.625 mg (CEE, n = 34), continuous combined CEE 0.625 mg plus medroxyprogesterone acetate (MPA) 5 mg, (n = 80), continuous combined 17beta-estradiol 2 mg plus norethisterone acetate (NETA) 1 mg (n = 58), tibolone 2.5 mg (n = 83) and raloxifene HCl 60 mg (n = 50). Forty-five postmenopausal women with no indications for HRT served as controls. Total cholesterol (TC), low-density lipoprotein (LDL) cholestrol and high-density lipoprotein (HDL) cholesterol, triglyceride (TG), apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB) and lipoprotein(a) (Lp(a)) levels were assessed in each subject at baseline, and at 6 and 12 months of therapy. All therapy regimens lowered TC levels compared to baseline (4.2-8.0% decrease). This effect was more prominent in the subgoup of women with high baseline TC levels (9.1-20.4% decrease). LDL cholesterol decreased significantly in CEE, CEE/MPA and raloxifene groups (-11.2%, -11.9% and -11.0%, respectively). Hypercholesterolemic women exhibited a steeper decrease in LDL cholesterol (10.6-27.8% in all therapy groups). TG levels increased significantly in the CEE and CEE/MPA groups (23.7% and 21.8%, respectively), while estradiol/NETA had no effect on TG levels. Tibolone decreased TG levels markedly, by 20.6%, while raloxifene had no TG-lowering effect. HDL cholesterol and ApoA1 were increased by CEE and CEE/MPA (HDL cholesterol, 7.4% and 11.8%, respectively; ApoA1, 17.8% and 7.9%, respectively) and decreased by tibolone (HDL cholesterol, -13.6%; and ApoA1, -9.9%). All therapy regimens except raloxifene lowered Lp(a) levels, with tibolone having the more pronounced effect (-13.2 to -29.0%). In conclusion, each therapy regimen had a diferent effect on lipid-lipoprotein levels, exerting favorable and unfavorable modifications. Hypercholesterolemic women seemed to benefit more from the cholesterol-lowering effect of estrogen replacement therapy/HRT. The choice for a particular regimen should be based on individual needs, indications and lipid-lipoprotein profile.

Breast pain and mammographic density increase as a consequence of raloxifene therapy.

A 55-yr-old post-menopausal woman with osteopenia and no history of breast disease is presented. She was placed on raloxifene HCl 60 mg and soon after developed severe breast pain. The follow-up mammogram, performed prematurely at 6 months, showed a marked increase in breast density. Therapy was accordingly stopped and mastodynia subsided. The patient's mammogram regressed to pre-treatment status after 6 months off-therapy.