The effect of hormone therapy and tibolone on serum CD40L and ADAM-8 in healthy post-menopausal women.

BACKGROUND/AIM: The role of neutrophils and platelets in atherothrombotic disease is well established. The aim of our study was to investigate the effect of HT and tibolone on the soluble markers of neutrophil and platelet activation, "a disentigrin and metalloproteinase domain" (ADAM-8) and CD40 ligand (CD40L) respectively, in healthy post-menopausal women. SUBJECTS AND METHODS: One hundred and six healthy post-menopausal women were randomly allocated to: estradiol plus drospirenone (E2/DSP), E2 hemihydrate 1 mg plus norethisterone acetate (E2/NETA) 0.5 mg, and tibolone 2.5 mg. Serum ADAM-8 and CD40L were measured at baseline and at 6 months. RESULTS: Baseline values of ADAM-8 and CD40L were similar between groups. No significant correlation was revealed between ADAM-8 or CD40L and parameters related to cardiovascular risk factors in each group. No significant changes were observed between baseline values and values at 6 months (E2/DSP group: ADAM-8: 267.4±71.3 pg/ml vs 270.7±42.8 pg/ml, p=0.86, CD40L: 6.43±3.13 vs 6.79±2.70 ng/ml, p=0.67), (E2/NETA group: ADAM-8: 308.3±64.3 vs 294.7±57.7 pg/ml, p=0.40, CD40L: 9.68±2.81 vs 8.59±5.13 ng/ml, p=0.51), (tibolone group: ADAM-8: 307.5±87.5 vs 289±48.1 pg/ml, p=0.48, CD40L: 9.46±4.30 vs 9.26±4.60 ng/ml, p=0.99). CONCLUSIONS: Our study has not revealed an association between estrogen plus progestin treatment or tibolone on serum ADAM-8 and CD40L levels in healthy post-menopausal women. Larger prospective studies are needed to further investigate the effect of low-dose HT or tibolone on serum markers of neutrophil and platelet activation.

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 17beta-estradiol 1 mg and norethisterone acetate 0.5 mg (E2/NETA, n = 43) or to 17beta-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.

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.

[A study of irritability in menopausal women].

Despite the fact that irritability is frequently the main presenting complaint of perimenopausal and postmenopausal women, studies specifically researching irritability in this population are scant. One hundred sixty three (163) peri- and postmenopausal women non-HT users, attending a menopause clinic, were included in this cross-sectional study. The investigation focused on whether the occurrence of inward and outward irritability in menopause is associated with various menopausal parameters, such as vasomotor symptoms, insomnia, menopausal status, hormone levels, and with the presence of chronic disease. Furthermore, we examined the possible association of inward and outward irritability with measures of anxiety and depression. Outward and inward irritability of peri- and postmenopausal women seem to be related to chronic disease, a factor that may be partially influenced by the older age of menopausal women. Outwardly directed irritability is found to be related to FSH and LH levels, independently of specific menopausal symptoms, such as vasomotor symptoms or insomnia. Outward irritability was found to be positively correlated with depressive symptomatology, whereas inward irritability correlated with both anxiety and higher depressive symptomatology.

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.

Doppler assessment of the intrauterine growth-restricted fetus.

The evaluation of fetal well-being by Doppler velocimetry in cases of intrauterine growth restriction (IUGR) is of great importance as it is very useful in detecting those IUGR fetuses that are at high risk because of hypoxemia. Several Doppler studies initially on fetal arteries and recently on the fetal venous system provide valuable information for the clinicians concerning the optimal time to deliver. Doppler sonography in combination with the other biophysical methods such as cardiotocogram and biophysical profile score should be used in everyday practice for the monitoring and appropriate management of the growth-restricted fetuses. The purpose of this review is to describe the current approaches in Doppler assessment of IUGR fetal circulation.

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.

Cardiovascular disease: screening and management of the a-symptomatic high-risk post-menopausal woman.

Menopause-related oestrogen deficiency increases the risk of cardiovascular disease (CVD). The presence of abdominal obesity, dyslipidemia, hypertension, fasting hyperglycaemia or impaired glucose tolerance further aggravates the CVD risk imposed by menopause. A detailed personal history should be recorded, covering PCOS, gestational diabetes mellitus, alcohol intake and smoking, as well as a family history of cardiovascular disease. Screening of the a-symptomatic post-menopausal woman should include fasting lipid profile, plasma glucose and liver, renal and thyroid function tests. Serum low-density lipoprotein cholesterol (LDL-c)>130 mg/dL is associated with an increased risk of CVD. Levels of triglycerides (TG)>or=150 mg/dL and high-density lipoprotein cholesterol (HDL-c)

Effect of hormone therapy on the elastic properties of the arteries in healthy postmenopausal women.

The aim of the study was to assess the effect of continuous hormone therapy (HT) for 1 yr on pulse wave analysis and central aortic pressure in healthy postmenopausal women. Sixty-five healthy postmenopausal women were randomly allocated to receive either conjugated equine estrogens 0.625 mg plus medroxyprogesterone acetate 5 mg (CEE/MPA, Premelle 5, Wyeth-Ayerst Lab, Philadelphia, PA, no.=32) or no therapy (no.=33). Treatment was continuous, and the study period lasted 12 months. Central aortic pressure, augmentation and augmentation index (AI) were determined non-invasively using applanation tonometry. All measurements were performed at baseline and at the end of the study by the same person. Ns differences were found between baseline values and values at the end of the study in either the control or the CEE/MPA group in central systolic aortic pressure (107.0 +/- 13.1 vs 107.6 +/- 11.3 mmHg, p=0.80, and 110.8 +/- 10.8 vs 112.3 +/- 11.4 mmHg, p=0.23, respectively), augmentation (12.6 +/- 4.2 vs 11.9 +/- 4.8 mmHg, p=0.45 and 11.7 +/- 3.7 vs 12.6 +/- 4.2 mmHg, p=0.34, respectively), and percentage of AI (36.8 +/- 9.3 vs 36.3 +/- 10.3, p=0.81 and 34.1 +/- 8.9 vs 34.9 +/- 9.8, p=0.72, respectively). The results of this preliminary report suggest that HT for 1 yr does not have any significant effect on central aortic pressure and wave reflection in healthy postmenopausal women.

Serum androgen levels and insulin resistance in postmenopausal women: association with hormone therapy, tibolone and raloxifene.

OBJECTIVE: To assess endogenous androgen and insulin resistance status in postmenopausal women receiving continuous combined hormone therapy (HT), tibolone, raloxifene or no therapy. METHODS: A total of 427 postmenopausal women aged 42-71 years were studied in a cross-sectional design. Among them 84 were taking HT (46 women conjugated equine estrogens 0.625 mg; medroxyprogesterone acetate, 5 mg, CEE/MPA; and 38 women 17beta-estradiol 2 mg; norethisterone acetate 1 mg, E2/NETA); 83 were taking tibolone 2.5 mg; 50 were taking raloxifene HCl 60 mg; and 210 women were not receiving any therapy. Main outcome measures were FSH, LH, estradiol, total testosterone, SHBG, free androgen index (FAI), Delta4-Androstendione (Delta4-A), Dehydroepiandrosterone sulphate (DHEAS) and HOMA insulin resistance index (HOMA-IR). RESULTS: In women not on hormone therapy smoking and older age was associated with lower DHEAS levels. FAI values increased linearly with increasing BMI. Age and BMI were positive determinants of HOMA-IR, while no association was identified between endogenous sex steroids and insulin resistance. CEE/MPA therapy was associated with higher SHBG, lower FAI and lower HOMA-IR values compared to women not on therapy (age and BMI-adjusted SHBG: CEE/MPA 148.8 nmol/l, controls 58.7 nmol/l, p < 0.01; age-adjusted FAI: CEE/MPA 0.8, controls 3.2, p < 0.05; age-adjusted HOMA-IR: CEE/MPA 1.3, controls 2.6, p < 0.05). On the contrary, E2/NETA treatment had no effect on these parameters. Women on tibolone had lower SHBG, higher FAI and similar HOMA-IR values compared to controls (age and BMI-adjusted SHBG: 24.1 nmol/l, p < 0.01; FAI: 6.0, p < 0.05; HOMA-IR: 2.3, p = NS). Raloxifene users did not exhibit any difference with respect to sex steroids and HOMA-IR levels. CONCLUSIONS: CEE/MPA users had lower free testosterone and improved insulin sensitivity. Tibolone on the other hand associated with higher free testosterone, while raloxifene did not relate to any of these parameters.

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.

Effect of hormone therapy, tibolone and raloxifene on circulating vascular endothelial growth factor in Greek postmenopausal women.

OBJECTIVE: To evaluate the effect of continuous combined hormone therapy (HT), tibolone and raloxifene on circulating vascular endothelial growth factor (VEGF) in postmenopausal women. DESIGN: One-year prospective intervention study. METHODS: One hundred and forty-six postmenopausal women with a mean age of 51.8+/-4.1 (s.d.) years received 0.625 mg conjugated equine estrogen (CEE) plus 5 mg medroxyprogesterone acetate (MPA) (CEE/MPA, n=34), 2.5 mg tibolone (n=37), 60 mg raloxifene (n=40) or no active treatment (control group, n=35). Plasma VEGF was estimated at baseline and at 6 and 12 months. RESULTS: In both the CEE/MPA-treated and the tibolone-treated groups plasma VEGF increased significantly at month 6 and remained elevated at month 12 (CEE/MPA baseline: 268.1+/-187.8 pg/ml, month 6: 320.0+/-175.3 pg/ml, month 12: 321.1+/-181.8 pg/ml, P=0.01; tibolone baseline: 240.6+/-165.8 pg/ml, month 6: 271.4+/-172.7 pg/ml, month 12: 274.8+/-183.1 pg/ml, P=0.03). These changes were significantly different from the respective changes in the control group after adjusting for T-score in bone densitometry (CEE/MPA: P=0.02, tibolone: P=0.04). The effect of HT or tibolone on plasma VEGF was mainly evident in women with low baseline VEGF levels (<243.2 pg/ml, median for whole sample). On the contrary, VEGF levels in the raloxifene-treated or the control group did not change throughout the study. CONCLUSION: Both continuous combined HT and tibolone increased circulating VEGF in postmenopausal women, while raloxifene had no effect. Further research is needed to clarify the clinical relevance of these findings with respect to cardiovascular risk in postmenopausal women.

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), 17beta-estradiol 2 mg plus norethisterone acetate 1 mg (E2/NETA, no. = 44), tibolone 2.5 mg (no. = 84), raloxifene HCI 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). LDL-C 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.

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, delta4androstendione, 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.

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.

Effects of estrogen-progestin and raloxifene therapy on nitric oxide, prostacyclin and endothelin-1 synthesis.

This randomized double-blind study was conducted to investigate the effects of 17 beta-estradiol plus norethisterone acetate, and raloxifene, on nitric oxide (NO), prostacyclin (PGI2) and endothelin-1 (ET-1) serum levels in postmenopausal women. Treatment was initiated after a 28-50 day placebo period. Fourteen women were treated daily with 17 beta-estradiol 2 mg plus norethisterone acetate 1 mg (E2 + NETA), and 14 with raloxifene HCl 60 mg for a period of 6 months. Serum NO, PGI2 and ET-1 levels were estimated at baseline, after placebo, and at months 3 and 6. E2 + NETA decreased NO levels significantly, while raloxifene did not cause any appreciable change. Both regimens decreased PGI2 levels and ET-1 levels significantly. Finally, E2 + NETA and raloxifene increased the NO/ET-1 ratio by 61.4% and 81.1%, respectively. In conclusion, both regimens may exert a cardio-protective effect by decreasing ET-1 levels and increasing the NO/ET-1 ratio. In contrast, both regimens had a negative influence on PGI2 levels.

Homocysteine and folate levels in postmenopausal women.

OBJECTIVES: To assess total homocysteine (tHcy) and folate levels in postmenopausal women and investigate whether age, menopause duration, kind of menopause and tobacco use had an effect on these levels. METHODS: Total homocysteine and folate levels were measured in fasting blood samples of 200 postmenopausal women with normal thyroid and renal function tests. Patients were not receiving vitamins or hormone replacement therapy. RESULTS: Total homocysteine levels increased significantly after 60 years while folate levels showed a decrease trend after 65 years. Menopause duration had no effect on folate levels and increased significantly tHcy levels after >180 months duration. The kind of menopause did not influence tHcy and folate levels. Tobacco use reduced significantly folate levels. CONCLUSIONS: Age seems to be the principal factor influencing tHcy levels. We believe that decreased folate levels also reflect an age-associated inadequate dietary intake. Tobacco use did not alter tHcy levels; however, we found smoking to lower folate levels.

Thyroid autoimmunity in patients with recurrent spontaneous miscarriages.

Recurrent spontaneous miscarriage (RSM) is a multifactorial problem. Auto- and alloimmune parameters have been implicated. Antithyroid antibodies (ATA) were tested in a group of women with RSM. The presence of antipaternal antibodies (APCA) was evaluated as an index of alloimmune contribution. Thirty euthyroid women with RSM (three or more consecutive miscarriages) aged 25-37 years were compared with 15 matched controls. Thyroid peroxidase (TPO) and thyroglobulin antibodies were tested with a chemiluminescence immunoassay and APCA were tested with a cross-match reaction. Results were compared using the chi-squared test. There was a higher frequency of ATA in women with RSM compared to controls (37% versus 13%, p < 0.05). Twenty of the women (67%) with RSM were tested negative for APCA, indicating an alloimmune contribution to their infertility. In this subgroup of women, the frequency of ATA continued to be higher than controls (40% versus 13%, p < 0.05). In conclusion, women with RSM, independent of APCA status, have a higher frequency of ATA. This may represent an additional marker for impaired regulation of the maternal immune system.