I. Lambrinoudaki

The Cardiovascular Effects of Selective Estrogen Receptor Modulators

Abstract:  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‐α 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.

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 raloxifene 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, climacteric 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 17β-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 different 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.

Effect of long-term valproate monotherapy on bone mineral density in adults with epilepsy

BACKGROUND We evaluated the cross-sectional relationship of duration and dosage of valproate monotherapy on bone mineral density (BMD) in adult patients with epilepsy. METHODS The BMD at lumbar level (L2-L4) was measured in consecutive adult epileptic patients receiving long-term (> or =2 years) valproate monotherapy by dual energy X-ray absorptiometry (DXA). Blood samples were collected for total serum calcium, phosphorus, magnesium, 25-hydroxyvitamin D(3) and parathormone. Osteopenia and osteoporosis were defined according to the World Health Organization operational BMD definition. Cross-sectional associations were evaluated using Spearmans correlation coefficient. RESULTS A total of 41 patients were studied (mean age 32.3+/-8.2 years, 12 men, mean duration of valproate monotherapy 10.6+/-7.4 years). Osteopenia was present in 24% of subjects, while no case of osteoporosis was documented. Duration and dosage of valproate monotherapy did not correlate with BMD. No association was documented between duration or dosage of valproate monotherapy and biochemical parameters. CONCLUSIONS Duration of valproate monotherapy does not correlate with decreased BMD in adult patients with epilepsy. No case of osteoporosis was identified in patients treated with valproate for a mean period of more than ten years. These findings indicate that bone metabolism may not be affected by valproate monotherapy.

Determinants of serum leptin levels in healthy postmenopausal women

The aim of this study was to evaluate factors that influence leptin levels in postmenopausal women. One hundred and forty-four postmenopausal women were evaluated cross-sectionally. In every woman a complete medical history was obtained, body mass index (BMI) was recorded and morning fasting blood was obtained for the determination of serum leptin, follicle stimulating hormone (FSH), estradiol, testosterone, Δ4androstendione, dehydroepiandrosterone sulphate (DHEAS) and insulin. In univariate analysis, age, BMI and insulin were positively correlated with serum leptin, while DHEAS showed a negative association with leptin concentrations (age r=0.21, p=0.005, BMI r=0.41, p=0.0001, insulin r=0.20, p=0.008, DHEAS r=−0.28, p=0.0001). In stepwise multivariate regression analysis serum leptin could be best predicted from BMI, serum insulin and serum DHEAS [leptin= (1.41 * BMI) −(0.01 * DHEAS) + (3.26 * insulin) −26.3; model r2=0.24, p=0.001]. In conclusion, BMI and serum insulin have a positive while serum DHEAS has a negative impact on serum leptin. Neither endogenous estradiol, nor endogenous testosterone are associated with leptin levels. Further studies are needed to elucidate the role of leptin in determining body weight and composition in postmenopausal women.

Menopausal symptoms are associated with subclinical atherosclerosis in healthy recently postmenopausal women

ABSTRACT Objectives To determine whether menopausal symptoms are associated with changes in arterial structure and function in healthy, recently postmenopausal women. Methods One hundred and ten postmenopausal women aged 45–55 years were included in the present cross-sectional study. Menopausal symptoms were recorded by the Greene Climacteric Scale. Anthropometric measures, blood pressure, serum lipids, glucose, insulin, sex and thyroid hormones were determined in each individual. Arterial structure, function and stiffness were assessed by intima–media thickness (IMT), flow-mediated dilation and pulse-wave velocity, respectively. Results Women with moderate to severe hot flushes had increased IMT compared to women with no or mild hot flushes (IMT in women with no hot flushes 0.61±0.08 mm, IMT in women with mild hot flushes 0.62±0.11 mm, IMT in women with moderate to severe hot flushes 0.67±0.11 mm; p = 0.034). This difference was independent of cardiovascular risk factors like age, menopausal age, smoking, blood pressure, adiposity, lipid levels, insulin resistance or hormone levels. No association was detected between psychological or psychosomatic symptoms and arterial indices. Furthermore, menopausal symptoms were not associated with serum sex steroids or thyroid hormone levels. Conclusions Carotid IMT, a surrogate marker of subclinical atherosclerosis and cardiovascular risk, was found to be increased in women with vasomotor symptoms as compared to asymptomatic women. This association was independent of cardiovascular risk factors or endogenous hormone levels. It remains to be elucidated whether the presence of menopausal symptoms is an additional cardiovascular risk factor requiring preventive intervention.

Circulating androgens are associated with mood disturbances in young postmenopausal women.

Abstract Objectives We aimed to evaluate the association between circulating androgens and the presence of psychological symptoms in a sample of healthy middle-aged women. Methods Psychological and depressive symptoms were evaluated in a total of 207 postmenopausal women, using the Symptom Checklist-90-R (SCL-90R) and the Zung Depression Scale, respectively. We investigated the associations between the SCL-90R and Zung Scale scores, and anthropometric, lifestyle parameters, as well as serum levels of androgens. Results The free androgen index was positively associated with scores of depression (b-coefficient ± standard error (SE) = 0.2 ± 0.2, p = 0.040), anxiety (b-coefficient ± SE = 0.2 ± 0.2, p = 0.028), anger/aggressiveness (b-coefficient ± SE = 0.3 ± 0.2, p = 0.026), psychotism (b-coefficient ± SE = 0.3 ± 0.1, p = 0.013) as well as with the global index of the SCL-90R scale (b-coefficient ± SE = 0.2 ± 0.1, p = 0.036), while sex hormone binding globulin was negatively associated with depression (b-coefficient ± SE = −0.2 ± 0.0, p = 0.046) and psychotism (b-coefficient ± SE = −0.2 ± 0.0, p = 0.047). These associations were independent of vasomotor symptomatology, smoking and hormone therapy intake and were more pronounced in younger (≤ 5.5 years) compared to older postmenopausal women. Levels of dehydroepiandrosterone sulfate were positively associated with interpersonal sensitivity (b-coefficient ± SE = 0.3 ± 0.3, p = 0.042), psychotism (b-coefficient ± SE = 0.4 ± 0.2, p = 0.007) and the global index (b-coefficient ± SE = 0.3 ± 0.2, p = 0.040) in women < 5.5 years postmenopausal. No significant associations were observed between the Zung or Greene Scale scores and levels of androgens. Conclusion Higher androgenicity was positively associated with symptoms of anxiety and depression in postmenopausal women. These associations were stronger in women closer to the menopausal transition, a finding which may suggest that menopause rather than aging may mediate the association of androgens with mood disorders.

Efficacy and safety of DT56a compared to hormone therapy in Greek post-menopausal women

Background: Hormone therapy (HT) is the treatment of choice for the alleviation of menopausal symptoms; concerns, however, about its concomitant long-term health risks have limited its use. DT56a is a unique enzymatic isolate of soybeans. The purpose of our study was to evaluate the efficacy and safety of DT56a, compared to HT, in symptomatic post-menopausal women. Subjects and methods: Eighty-nine post-menopausal women were studied prospectively. Women with climacteric symptoms were randomly assigned to receive eitherDT56a (no.=27) or oral low dose continuous combined HT (no.=26). Symptomatic women not wishing to receive any treatment served as controls (no.=36). Menopausal symptoms as assessed through the Kupperman index, serum lipids and lipoproteins, calcium, as well as bone mineral density (BMD), endometrial thickness, and mammography were assessed at baseline and at 12 months. Results: Patients receiving HT and DT56a showed a significant and independent decrease in menopausal symptoms (mean difference in Kupperman score, DT56a group: −3.98, HT group −5.601, no treatment group +1.76, p-value <0.001). Lumbar spine BMD T-score was significantly lower in women receiving no treatment, as opposed to the two treatment arms which showed no significant change (No treatment, baseline: −0.60, final: −0.85, p=0.001; HT, baseline: −84, final −0.99, p=0.79; DT56a, baseline −0.51, final: −0.76, p=0.75). No differences in femoral bone density, ET or mammography classification were detected in any of the treatment arms. Likewise, serum lipids or lipoproteins did not differ between the three groups. Conclusions: DT56a decreased menopausal symptoms significantly and in the same degree as HT.

Prevalence of vasomotor, psychological, psychosomatic and sexual symptoms in perimenopausal and recently postmenopausal Greek women: association with demographic, life-style and hormonal factors

Aim: To assess the prevalence of climacteric symptoms and their association with demographic, life-style and hormonal parameters in Greek peri- and recently postmenopausal women. Methods: 1025 Greek women who were either perimenopausal or within their first 5 postmenopausal years participated in this cross-sectional observational study. Menopausal symptoms were assessed by the Greene Climacteric Scale and were tested for associations with demographic, anthropometric, life-style and hormonal parameters. Results: 29.8% Of the women reported moderate to severe menopausal symptoms. More specifically, 39.2% reported vasomotor, 21.3% psychological, 6.3% psychosomatic and 34.5% sexual symptoms. Years since menopause (r = 0.13, p < 0.01), waist circumference (r = 0.11, p < 0.05) as well as serum FSH, LH and estradiol (r = 0.15, r = 0.118, r = −0.157; p < 0.01) correlated with the intensity of menopausal symptoms. In the multivariate analysis years since menopause and serum estradiol were the only significant predictors of menopausal symptoms (b = −0.158 and b = −0.198, p < 0.001, respectively), explaining though only 4.8% of the variance. Conclusion: One out of three Greek women has moderate to severe climacteric symptoms during the menopause transition or the first postmenopausal years. This frequency is comparable to other White populations. Menopausal age and endogenous estrogens are significant predictors of climacteric symptoms.

Serum lipids and apolipoproteins in Greek postmenopausal women: Association with estrogen, estrogen-progestin, tibolone and raloxifene therapy

The aim of this study was to assess lipid and apolipoprotein levels in postmenopausal women taking various regimens of replacement therapy or no therapy. Seven hundred forty-eight postmenopausal women followed in the Menopause Clinic of the 2nd Department of Obstetrics and Gynecology, University of Athens, Aretaieion Hospital, were studied in a cross-sectional design. Women were either non-users of replacement therapy (no.=511) or users of one of the following regimens: conjugated equine estrogen 0.625 mg (CEE, no.=34), CEE 0.625 mg plus medroxyprogesterone acetate 5 mg (CEE/MPA, no.=60), 17β-estradiol 2 mg plus norethisterone acetate 1 mg (E2/NETA, no.=44), tibolone 2.5 mg (no.=84), raloxifene HCl 60 mg (no.=51). Total cholesterol (TC), LDL-cholesterol (LDL-C) and HDL-cholesterol (HDL-C), triglycerides (TG), apolipoprotein A1 (ApoA1) and apolipoprotein B (ApoB) levels were assessed. Women were grouped according to replacement regimen and mean levels of lipid and apolipoproteins were compared between groups. Women in the raloxifene group were older and longer menopaused. After adjustment for age and duration of menopause, TG levels were significantly lower in the tibolone and E2/NETA groups (75 and 89.9 mg/dl, respectively) compared to non-users. TC was lower in all therapy groups, but the difference acquired significance only in the E2/NETA (207.8 mg/dl), compared to non-users (231.5 mg/dl). LDLC levels were significantly lower in the CEE (133.8 mg/dl), CEE/MPA (130.4 mg/dl) and raloxifene group (129.9 mg/dl) compared to non-users (151.9 mg/dl). There was no difference in HDL-C levels between users and non-users (58.9 mg/dl) except for the tibolone group where HDL-C was significantly lower (48.6 mg/dl). ApoA1 levels were significantly higher in the CEE/MPA group (194.4 mg/dl) and significantly lower in the tibolone group (141.6 mg/dl) compared to non-users (170.4 mg/dl). No difference was detected between groups concerning ApoB levels. In conclusion, tibolone therapy is associated with lower TG levels as well as lower HDL and ApoA1 levels. ERT, continuous combined estrogen-progestin therapy (HRT) and raloxifene are associated with lower LDL-C levels. Among continuous combined HRT users, CEE/MPA is associated with higher ApoA1 levels, while E2/NETA with lower TG levels. Large prospective randomized studies are required to validate these results.

Progestin may modify the effect of low-dose hormone therapy on mammographic breast density

Objectives To evaluate the effect on breast density of two low-dose hormone therapy regimens identical in their estrogen component but different in the progestin. Methods A total of 81 non-hysterectomized postmenopausal women were allocated either to 17β-estradiol 1 mg and norethisterone acetate 0.5 mg (E2/NETA, n = 43) or to 17β-estradiol 1 mg and drospirenone 2 mg (E2/DRSP, n = 38). Treatment was continuous and lasted 12 months. The main outcomes were the changes in breast density according to the Wolfe classification between baseline and 12-month mammograms. Results Involution of the fibroglandular tissue was not seen in either of the treatment groups. Under E2/NETA, breast density increased in seven women (16.3%). In contrast, only three women (7.9%) exhibited a density increase under E2/DRSP. Conclusions Although hormone therapy appears to suspend breast involution, it does not increase breast density in the majority of treated women. Progestins differing in pharmacological properties may have a variable impact on breast density.