Retinol-binding protein 4 is associated with arterial stiffness in early postmenopausal women.

OBJECTIVE: Recent evidence in postmenopausal women suggested lack of association between serum levels of retinol-binding protein 4 (RBP4) and subclinical atherosclerosis; however, associations with arterial stiffness in this population remain unexplored. We evaluated the association among RBP4 and cardiovascular risk factors, including homocysteine, a marker involved in retinoic acid synthesis, and indices of arterial stiffness, in a sample of apparently healthy postmenopausal women. METHODS: This cross-sectional study included 123 healthy postmenopausal women, not on hormone therapy, antihypertensive, or hypolipidemic treatment and with a menopausal age 10 years or less. We performed biochemical/hormonal assessment and sonographic evaluation, including carotid-femoral pulse wave velocity (PWV) and carotid artery stiffness index (SI). RESULTS: Univariate analysis showed that RBP4 values correlated with age, low-density lipoprotein-cholesterol and estradiol levels. There was a trend of association of SI and PWV with homocysteine and triglycerides. RBP4 differed according to PWV, using the median PWV value as cut-off (RBP4, PWV ≤8.1 vs >8.1 m/s: 10.09 ±â€Š2.05 vs 10.85 ±â€Š1.91 ng/mL, analysis of covariance P value 0.014 adjusted for age, menopausal age, estradiol, pulse pressure). Linear regression analysis showed that PWV was independently associated with RBP4, age, and pulse pressure, whereas SI was independently associated with RBP4. An increase of one standard deviation in RBP4 levels (2.54 ng/mL) was associated with an increase of 0.577 m/s in PWV. CONCLUSIONS: RBP4 serum levels are associated with arterial stiffness, in a sample of healthy postmenopausal women. If this association is causative, serum RBP4 levels could serve as a marker of arterial stiffness. Prospective studies are required to investigate the significance of our findings. : Video Summary:http://links.lww.com/MENO/A621.

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Measurable serum markers of oxidative stress response in women with endometriosis.

OBJECTIVE: To evaluate the hypothesis of increased systemic oxidative stress in patients with endometriosis. SETTING: Tertiary care university hospital. DESIGN: Cross-sectional study. PATIENT(S): Sixty-six women of reproductive age undergoing laparoscopy. INTERVENTION(S): All women were investigated for endometriotic foci during laparoscopy. Forty-five women had laparoscopically and histologically confirmed endometriosis, and 21 women did not have endometriosis. MAIN OUTCOME MEASURE(S): Four markers of oxidative stress were assessed in the serum of each patient: heat shock protein 70 (HSP70), HSP70b', thioredoxin (TRX), and ischemia-modified albumin (IMA). RESULT(S): Mean serum HSP 70b' level was higher in patients with endometriosis compared with controls (0.178 ng/mL, SD 0.103, and 0.135 ng/mL, SD 0.014, respectively). The disease stage did not affect HSP70b' levels. Heat shock protein 70, IMA, and TRX levels did not differ between patients with endometriosis and controls. Women with a history of arterial hypertension had higher mean IMA levels compared with women with normal blood pressure independently of the presence of endometriosis (106.7 [SD 25.4] U/mL and 85.0 [SD 11.5] U/mL, respectively). CONCLUSION(S): Endometriosis is associated with increased systemic oxidative stress. The implication of increased systemic oxidative stress in disease progression or the association with other oxidative stress-related pathologic conditions needs to be addressed in further studies.

CYP A-204C polymorphism is associated with subclinical atherosclerosis in postmenopausal women.

OBJECTIVE: To assess the association of common polymorphisms involved in lipoprotein oxidation, platelet activation, and cholesterol and homocysteine metabolism with subclinical atherosclerosis and indices of endothelial function and arterial elasticity in healthy postmenopausal women. DESIGN: The study investigated 84 healthy postmenopausal women recruited from the Menopause Clinic of the 2nd Department of Obstetrics and Gynecology, University of Athens, Aretaieion Hospital. The following polymorphisms were genotyped: apolipoprotein B 3500, apolipoprotein E (E2/E3/E4), cholesterol 7 alpha-hydroxylase A-204C (CYP A-204C), cholesterol ester transfer protein B1/B2, glycoprotein IIIa leu33pro, integrin beta 3 PLA1/PLA2, plasminogen activator inhibitor 1 4G/5G, paraoxonase 1 gln192 arg, and methylenetetrahydrofolate reductase ala222val. Ultrasound examination aimed to assess the presence of atherosclerotic plaque and to measure intima-media thickness in the carotid and femoral arteries and to estimate the augmentation index, brachial flow-mediated dilatation, and radial and femoral pulse-wave velocity. RESULTS: The cholesterol 7 alpha-hydroxylase A-204C polymorphism was positively associated with the presence of atherosclerotic plaque (P = 0.004) and carotid and femoral intima-media thickness (P = 0.047 and P = 0.025, respectively). CONCLUSIONS: The CYP A-204C polymorphism was positively associated with subclinical atherosclerosis in healthy postmenopausal women. It remains to be clarified whether the presence of these polymorphisms may be valuable in assessing the inherent risk among postmenopausal women.

Circulating leptin and ghrelin are differentially influenced by estrogen/progestin therapy and raloxifene.

BACKGROUND: Leptin and ghrelin are increasingly being recognized as cardiotropic hormones, promoting or inhibiting the atherosclerotic process, respectively. Apoptosis may be one pathway through which the actions of these hormones are mediated. Sex hormones are reported to influence the secretion and action of ghrelin and leptin. OBJECTIVE: To evaluate (1) the association of circulating ghrelin and leptin with selected markers of receptor-mediated apoptosis and (2) the effect of estrogen monotherapy, low dose estrogen-progestin therapy, tibolone and raloxifene on serum ghrelin and leptin in healthy postmenopausal women. METHODS: Eighty eight postmenopausal women aged 44-62 years were randomly allocated to daily (1) conjugated equine estrogens 0.625 mg (CEE), (2) 17beta-estradiol 1mg plus norethisterone acetate 0.5 mg (E(2)/NETA), (3) tibolone 2.5mg, (4) raloxifene HCl 60 mg or (5) no treatment. Serum markers of apoptosis sFas, Fas-ligand (Fas-L) and caspase-1 were measured at baseline. Serum leptin and ghrelin were measured at baseline and at 3 months. RESULTS: Body Mass Index (BMI) and estradiol levels correlated positively, while FSH correlated negatively with serum leptin (BMI: r=0.646, p=0.005, estradiol: r=0.432, p=0.001, FSH: r=-0.401, p=0.002). Insulin levels associated positively with circulating leptin (r=0.394, p=0.011) and negatively with circulating ghrelin (r=-0.401, p=0.009). Serum leptin decreased significantly in E2/NETA group (baseline: 2.882+/-0.76 ng/ml, 3 months: 2.687+/-0.66 ng/ml, p=0.043), while it increased significantly in the raloxifene group (baseline: 2.671+/-0.54 ng/ml, 3 months: 2.839+/-0.47 ng/ml). Ghrelin levels decreased significantly only in the raloxifene group (baseline: 1634+/-592 pg/ml, 3 months: 1408+/-534 pg/ml). CONCLUSION: Apoptosis may be a pathway through which leptin exerts a pro-atherogenic effect. Low dose HT may act cardioprotectively by decreasing leptin levels in healthy recently menopaused women.

Circulating chemoattractants RANTES, negatively related to endogenous androgens, and MCP-1 are differentially suppressed by hormone therapy and raloxifene.

BACKGROUND: The cardinal role of chronic inflammation in the development of atherosclerosis is increasingly being recognized. Estrogens may prevent the evolution of atherosclerosis by suppressing immune response. Furthermore, the conflicting reports on the cardiovascular effects of hormone therapy between observational and clinical trials have triggered interest on the effect of alternative therapies on the cardiovascular system. OBJECTIVE: The aim of this study was to assess the effect of estrogen, estrogen-progestin, tibolone and raloxifene therapy on circulating markers of chemotaxis in healthy postmenopausal women. METHODS: Eighty-eight postmenopausal women aged 44-62 years were randomly allocated to daily: (1) conjugated equine estrogens 0.625 mg (CEE), (2) 17beta-estradiol 1mg plus norethisterone acetate 0.5mg (E(2)/NETA), (3) tibolone 2.5mg, (4) raloxifene HCl 60 mg or (5) no treatment. Serum monocyte chemoattractant protein-1 (MCP-1) and regulated upon activation, normal T-cell expressed and secreted (RANTES) were measured at baseline and at 3 months. RESULTS: Endogenous testosterone and free androgen index (FAI) correlated negatively, while SHBG correlated positively with serum RANTES (testosterone: r=-0.27, p=0.033; FAI: r=-0.43, p=0.004: SHBG: r=0.34, p=0.026). Serum MCP-1 decreased significantly in the CEE group (baseline 125.3+/-51 pg/ml, 3 months 84.5+/-36.1 pg/ml, p=0.043), while no difference was detected between baseline and post-treatment levels in the other groups. Furthermore, a significant decrease in serum RANTES was observed at the end of 3 months only in the E2/NETA and the raloxifene group (E2/NETA baseline 8690.6+/-3880.0 pg/ml, 3 months 6894.0+/-1720.0 pg/ml, p=0.007; raloxifene baseline 9042.4+/-3765.6 pg/ml, 3 months 6718.1+/-2366.2 pg/ml, p=0.011). CONCLUSION: Endogenous androgens may suppress chemotactic response. Postmenopausal hormone therapy and raloxifene may inhibit the expression of chemoattractant molecules and thus attenuate inflammation. The relevance of these findings in terms of clinically established caridoprotection remains to be clarified.

Quality of life and psychological symptoms in Greek postmenopausal women: association with hormone therapy.

Quality of life (QoL) in menopause is influenced by many parameters, including vasomotor symptoms, psychological status and culture. The aim of the present study was to examine the association of hormone therapy (HT) with QoL and psychological symptoms in Greek postmenopausal women. The study assessed 216 postmenopausal women (mean age 54.5 years) attending a university menopause clinic in Greece. Fifty-three were users of HT and 163 were not. QoL was evaluated by the Utian Quality of Life Scale (UQOL) and psychological symptoms were assessed by the Symptom Checklist-90-R (SCL-90-R). Women on HT were younger and more educated than women not using HT. Adjusting the analysis for the women's characteristics, HT users had better total UQOL scores than non-users (p < 0.05). Marital status and education had independent effects on QoL, with married and more educated women scoring higher (p < 0.05). Assessment of psychological symptomatology, after adjustment for sociodemographic variables across the different dimensions, revealed that HT users had better SCL-90-R scores than non-users for obsessionality, interpersonal sensitivity and for the general index (p < 0.05). Concluding, even though the impact of sociodemographic and lifestyle variables must be factored into the assessment of QoL, HT use is independently related to an improvement in the total score and in most domains of QoL, and has a significant positive effect on many aspects of psychological well-being in Greek postmenopausal women.

Differential effect of hormone therapy and tibolone on lipids, lipoproteins, and the atherogenic index of plasma.

The aim of our study was to assess the effect of various regimens and doses of hormone therapy and tibolone on the Atherogenic Index of Plasma (AIP). A total of 519 postmenopausal women attending our menopause clinic were studied in a prospective design. Women with climacteric symptoms were randomly assigned to receive 1 of the following regimens: tibolone 2.5 mg, conjugated equine estrogens 0.625 mg plus medroxyprogesterone acetate 5 mg (CEE/MPA), 17beta-estradiol 2 mg plus norethisterone acetate 1 mg (E2/NETA), or 17beta-estradiol 1 mg plus norethisterone acetate 0.5 mg (low E2/NETA). Serum parameters were assessed at baseline and after 6 months and included total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, apolipoprotein A1 and apolipoprotein B. The AIP was assessed as the log (triglycerides [mmol/L]/HDL-C [mmol/L]). CEE/MPA treatment associated with lower mean LDL-C but higher mean triglyceride levels (-15.5 mg/dL +/- 3.6, P = 0.0001; 12.6 mg/dL +/- 4.8, P = 0.01). Furthermore, CEE/MPA treatment resulted in higher AIP levels (0.073 +/- 0.021, P = 0.001). On the contrary, both E2/NETA regimens and tibolone associated with lower mean triglyceride and HDL-C levels (E2/NETA, triglycerides: -9.8 mg/dL +/- 5.0, P = 0.049; HDL-C: -4.9 mg/dL +/- 1.8, P = 0.01, low E2/NETA triglycerides: -12.5 mg/dL +/- 4.1, P = 0.003; HDL-C: -4.7 mg/dL +/- 1.3, P = 0.001; tibolone, triglycerides: -21.9 mg/dL +/- 2.7, P = 0.0001; HDL-C: -12.7 mg/dL +/- 1.1, P = 0.0001). None of the 3 regimens had any effect on AIP. The effect of a particular regimen of hormone therapy on the lipid-lipoprotein profile differs depending on the parameter assessed. The use of unified markers such as AIP will be helpful in evaluating the overall effect of lipid-lipoprotein modulation on the cardiovascular system. In fact, the concurrent assessment of the therapy effect on both LDL-C and AIP may be more dependable in evaluating the cardiovascular impact of a given regimen.

Endogenous sex steroids and circulating homocysteine in healthy Greek postmenopausal women.

OBJECTIVE: The determinants of serum homocysteine in healthy postmenopausal women remain uncertain. The aim of this study was the assessment of the association of endogenous sex steroids with serum homocysteine levels in healthy postmenopausal women not on hormone therapy. DESIGN: 484 postmenopausal women aged 43-69 years were studied in a cross-sectional design. Parameters assessed were serum FSH, estradiol, total testosterone, SHBG, Free Androgen Index, delta4-Androstendione, Dehydroepiandrosterone sulphate, and homocysteine. RESULTS: Serum FSH correlated positively (r=0.23, p=0.01), while serum estradiol correlated negatively (r=-0.25, p=0.03) with circulating Hcy. This association remained statistically significant after adjustment for age, years since menopause, and BMI. Serum estradiol decreased, while FSH increased linearly with increasing homocysteine quartiles (p=0.04 and p=0.02, respectively). None of the serum androgens assessed correlated with circulating homocysteine. CONCLUSIONS: Endogenous estrogens and not androgens are related to serum homocysteine values in postmenopausal women. Whether this association has clinical implications remains to be clarified.

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.

The effect of low dose hormone therapy on mammographic breast density.

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

Effect of oral contraceptive treatment on bone mass acquisition in skeletally immature young female rats.

The objective of the present study was to investigate the effect of oral contraceptive (OC) treatment on bone mass accrual in skeletally immature young female rats. Animals in the baseline group were killed at the beginning of the experiment and were subjected to bone density assessment by peripheral quantitative computerized tomography (pQCT). The control group was fed a base diet free of phytoestrogens, while animals in the contraceptive group received the same base diet mixed with 2.67 microg desogestrel/100 g body weight and 0.0533 microg ethinyl estradiol/100 g body weight. The duration of the treatment period was 16 weeks. Densitometric measurements by dual energy x-ray absorptiometry and serum bone markers assessment were carried out at baseline, at 8 weeks and at 16 weeks, while pQCT densitometry took place after sacrifice. All bone mineral density and bone mineral content indices measured by dual energy x-ray absorptiometry increased significantly throughout the study period in both the OC and control group. Concerning pQCT measurements, animals in both the OC and the control group had significantly higher cortical density compared with baseline (midtibia: p=.0003 and .0003, respectively). Total area and periosteal circumference were significantly higher in OC group, both in proximal (p=.003 and .003, respectively) and midtibia (p=.048 and .042, respectively) compared with baseline. Osteoprotegerin serum levels increased in both groups, and at the end of the experiment, circulating osteoprotegerin was significantly higher in the OC group compared with controls (p=.032). At the end of the experiment, carboxyl-terminal telopeptides of collagen type I levels were significantly lower in the OC-treated animals compared with controls (p=.046). Our results suggest that OC administration to skeletally immature female rats allows normal bone accrual and may even improve bone geometry. This effect may be mediated through enhanced inhibition of bone resorption.

Effect of hormone replacement therapy and tibolone on serum leptin levels in postmenopausal women.

OBJECTIVE: To evaluate the effect of estrogen replacement therapy (ERT), continuous combined hormone replacement therapy (HRT) and tibolone on serum leptin levels in healthy postmenopausal women. METHODS: Eighty-four healthy postmenopausal women aged 43-63 years were studied prospectively. Hysterectomized women (n = 16) received conjugated equine estrogens (CEE) 0.625 mg. Women with an intact uterus were randomly allocated either to CEE+medroxyprogesterone acetate (CEE/MPA) 5 mg or tibolone 2.5 mg. Serum leptin levels were assessed at baseline and after 6 months of treatment. RESULTS: The three groups did not differ with respect to age, body mass index (BMI) or baseline serum leptin levels. Overweight women (BMI > 25 kg/m2) had higher baseline leptin levels (27.0 +/- 11.4 ng/ml) compared to their lean counterparts (BMI < or = 25 kg/m2; leptin: 16.5 +/- 8.1 ng/ml, P = 0.0001). Neither CEE nor CEE/MPA had any effect on serum leptin levels at the end of 6 months either in overweight or in lean women (overweight: CEE baseline 34.4 +/- 13.3 ng/ml, 6 months 36.9 +/- 15.8, P = 0.89, CEE/MPA baseline 22.4 +/- 9.8 ng/ml, 6 months 26.8 +/- 8.7 ng/ml, P = 0.1; lean: CEE baseline 12.6 +/- 4.4 ng/ml, 6 months 13.2 +/- 5.8 ng/ml, P = 0.36, CEE/MPA baseline 17.2 +/- 10.6 ng/ml, 6 months 18.8 +/- 8.8 ng/ml, P = 0.31). Similarly serum leptin remained unchanged at the end of the study in both lean and overweight women on tibolone (overweight: baseline 22.9 +/- 8.1 ng/ml, 6 months 18.5 +/- 12 ng/ml, P = 0.37; lean: baseline 13.2 +/- 5.6 ng/ml, 6 months 17.3 +/- 8.4 ng/ml). CONCLUSION: BMI is a strong determinant of serum leptin levels in healthy postmenopausal women. Neither ERT/HRT nor tibolone exert any effect on serum leptin after 6 months in lean or overweight postmenopausal women. Further studies are required to verify the exact role of estrogen and tibolone on leptin production and function in postmenopausal women.

The effect of hormone therapy and raloxifene on serum matrix metalloproteinase-2 and -9 in postmenopausal women.

OBJECTIVE: The aim of the study was to investigate the effect of continuous-combined hormone therapy and raloxifene on the total and active forms of serum matrix metalloproteinase (MMP) -2 and -9. DESIGN: The study was double-blinded, with a placebo run-in period of 28 to 50 days. Twenty-eight women received either 17beta-estradiol 2 mg + norethisterone acetate 1 mg (E2/NETA) or raloxifene HCL 60 mg for a period of 6 months. Total and active forms of MMP-2 and -9 were estimated at baseline and at month 6. RESULTS: Total MMP-2 increased significantly in both E2/NETA and raloxifene groups (raloxifene baseline: 278.1 +/- 18.1 ng/mL; 6 months: 303.1 +/- 29.9 ng/mL, P = 0.008) (E2/NETA baseline: 281.9 +/- 27.5 ng/mL; 6 months: 298.8 +/- 12.7 ng/mL, P = 0.025). Similarly, both treatments increased the active MMP-2 fraction, although only the raloxifene-associated increase acquired significance (raloxifene baseline: 24.9 +/- 8.6 ng/mL; 6 months: 31.6 +/- 15.3 ng/mL, P = 0.045) (E2/NETA baseline: 21.7 +/- 5.7 ng/mL; 6 months: 27.4 +/- 5.8 ng/mL, P = 0.128). Total as well as active fractions of MMP-9 were not significantly affected by either treatment. CONCLUSIONS: Both E2/NETA and raloxifene increased the total and active MMP-2 serum levels. MMP-9 was not significantly affected by either regimen. Larger, long-term clinical trials are needed to elucidate the effect of HT and raloxifene on MMPs and the possible clinical implications for cardiovascular health.

Effect of hormone replacement therapy and tibolone on serum total homocysteine levels in postmenopausal women.

OBJECTIVE: To assess the effect of continuous combined hormone replacement therapy (HRT) or tibolone on serum total homocysteine (tHcy) levels in postmenopausal women. STUDY DESIGN: Ninety-five postmenopausal women aged 41-68 years were included in the study. Seventy-three women with climacteric complaints, osteopenia or osteoporosis received either conjugated equine estrogens 0.625 mg combined with medroxyprogesterone acetate 5 mg (CEE/MPA, n=31) or tibolone 2.5 mg (n=42). Twenty-two healthy women, matched for chronological and menopausal age, served as controls. Serum tHcy levels were assessed at baseline, 6, 12 and 18 months. RESULTS: No difference was recorded between groups regarding demographic characteristics or mean baseline serum tHcy. Serum tHcy levels decreased significantly in the CEE/MPA compared to baseline (change at 18 months: -3.9%, P<0.05). The magnitude of the decrease was higher in the subgroup of women with baseline tHcy levels above the median (change at 18 months: -15.0%, P<0.01). No change in tHcy levels was detected in the tibolone group throughout the study period, either in the whole group (change at 18 months: 1.9%, NS) or in the subgroup with baseline tHcy levels above the median (change at 18 months: -3.23%, NS). CONCLUSION: Continuous CEE/MPA reduces tHcy especially in women with high pretreatment tHcy levels. Tibolone has no effect on serum tHcy levels at least during the first 18 months of therapy. Larger studies with longer follow-up are required to confirm these results.

The effect of various regimens of hormone replacement therapy on mammographic breast density.

OBJECTIVES: To evaluate the effect of three distinct hormone replacement therapy regimens on mammography. METHODS: 121 postmenopausal women who had never received or were past users of hormone replacement therapy were studied prospectively. Women with an intact uterus were randomly allocated either to conjugated equine estrogens 0.625 mg plus medroxyprogesterone acetate 5 mg (CEE/MPA, n=34) or to 17beta-estradiol 2 mg plus norethisterone acetate 1 mg (E(2)/NETA, n=35). Hysterectomized women received CEE 0.625 mg (CEE, n=25). Women who either declined or did not qualify for treatment served as controls (n=27). Treatment was continuous and the study period lasted 12 months. Main outcome measures were the changes according to Wolfe classification between baseline and 12-month-mammograms. RESULTS: No increase in breast density was identified in any of the women in the control group. Two women (8%) in the CEE group showed an increase in breast density. Four women (11.8%) in the CEE/MPA and 11 women (31.4%) in the E(2)/NETA group revealed an increase in breast density. No woman in the therapy groups showed an involution of fibroglandular tissue while seven women (25.9%) in the control group exhibited involution of breast parenchyma. CONCLUSIONS: Our study suggests that hormone replacement therapy may suspend breast involution but does not increase breast density in the majority of patients. In the minority of patients who show a density increase, the magnitude of this increase varies according to the regimen employed.

Body composition in asymptomatic HIV-infected men: cross-sectional and prospective assessment.

Data on body composition changes in HIV infected patients is sparse and controversial. The aim of this study was to assess body composition in asymptomatic HIV-infected men with normal body weight in comparison to healthy HIV-negative control men and to investigate possible body composition changes in HIV-positive patients over a 2-year observation period. One hundred eight asymptomatic seropositive men, aged 19-62 years, and 20 healthy sex, age and weight - matched controls were recruited for the cross-sectional part of the study. Fifty-eight of the HIV+ patients were followed up for 2 years. Body weight, BMI, Bone Mineral Content (BMC), body Fat mass (Fat), % Fat, body Lean mass (Lean) and % Lean was recorded for each subject at the beginning and at the end of the follow-up period. The same analysis was repeated separately for arms, trunk and legs. HIV+ men had increased fat mass and reduced lean mass compared to controls (%Fat in HIV+ 24.3, %Fat in controls 19.2, p=0.012; %Lean in HIV+ 72.1, %Lean in controls 77.0, p=0.014). Lean mass was lower in extremities while fat mass was higher in the trunk region in HIV+ in comparison to controls, irrespective of antiretroviral therapy. Longitudinally, patients with higher baseline %Fat (>24.2, median) presented 20% decrease in fat mass while patients with lower baseline %Fat (< or =24.2) showed a smaller, non-significant decrease in fat mass accompanied by a significant decrease (2.52%) in lean mass. Fat loss occurred in all subjects predominantly in the extremities (16.5-36.45% loss), with relative preservation of trunk fat. It is concluded that otherwise asymptomatic HIV+ men exhibit subtle body composition changes involving reduced lean mass and increased central fat mass. The pattern of weight loss over time depends on baseline fat store: patients with adequate fat stores lose predominantly fat while patients with lower baseline fat stores lose both fat and lean mass. In the entire cohort, there is a tendency towards central adiposity, with the majority of fat being lost from the extremities, a picture resembling metabolic x syndrome.

Macroprolactinemia. Is treatment necessary?

A 26-year old symptom-free woman was admitted to our Clinic for evaluation of hyperprolactinemia. The patient, who had normal menstrual cycles, was found accidentally to have a cystic adnexal mass and was placed on oral contraceptives (OC) for 3 months. During the first OC-cycle a bilateral breast nipple discharge was noticed and an elevated serum prolactin (PRL) was detected (2.7 nmol/l). The OC was discontinued and bromocriptine therapy was started. Serum PRL levels were restored and spontaneous menses resumed. The Pituitary magnetic resonance imaging (MRI), the anterior pituitary function, assessed by dynamic tests, and the thyroid hormone levels were normal. Upon bromocriptine discontinuation, PRL levels increased to 13.8 nmol/l. Poly-ethylene-glycol precipitation of the patient's serum, in two consecutive measurements, demonstrated the presence of macroprolactinemia. Since the patient was asymptomatic, a dopamine agonist was not resumed. Macroprolactinemia is characterized by most authors, as a benign condition with no clinical implications. However, a number of investigators challenge this view, suggesting that in some cases mild symptomatology is present possibly requiring therapeutic intervention.

Mammographic changes associated with raloxifene and tibolone therapy in postmenopausal women: a prospective study.

OBJECTIVE: The prolonged use of estrogen therapy is associated with a slightly increased risk of breast cancer. Alternative therapies that are effective in the prevention of menopause, having associated morbidities but no unwanted effects, are of primary interest in the pharmacologic research. The aim of this study was to evaluate the effect of two alternative to estrogens drugs, the selective estrogen receptor modulator raloxifene and the tissue-specific tibolone, on the mammographic appearance of the breast. DESIGN: The study group comprised 131 postmenopausal women aged 41 to 67 years. The women were at least 2 years postmenopausal, free of climacteric symptoms, and at the time of entry to the study had not had therapy for at least 9 months. Women with risk factors for osteoporosis or cardiovascular disease were allocated either to tibolone (n = 56) or raloxifene (n = 48) therapy. Women with no risk factors and women who either did not qualify for or denied treatment (n = 27) served as controls. The study duration was 12 months. Women received a baseline mammogram before commencing therapy and a repeat mammogram at the end of the study period. Mammogram findings were classified according to the modified Wolfe criteria by two expert radiologists. RESULTS: No difference was identified between groups with respect to baseline characteristics associated with breast cancer risk. Similarly, no difference was detected between groups concerning the modified Wolfe classification of baseline mammographic findings. In the tibolone group, 10.7% of the women showed an increase in breast density in the 12-month reevaluation. The respective figure in the raloxifene group was 6.3%, whereas no woman in the control group showed an increase in breast density. Differences in the increase in breast density between groups did not, however, reach statistical significance. Accordingly, 10.7% of women in the tibolone group and 18.8% of women in the raloxifene group exhibited involutionary changes in the repeat mammogram, whereas 25.9% of women in the control group revealed a decrease in breast density in the 12-month examination. The percentages were not significantly different between groups. CONCLUSIONS: Breast density as shown by mammography was stable in a majority of patients and changed in a minority of cases for both tibolone and raloxifene. In most patients, these drugs are not likely to interfere with mammogram interpretation. Larger long-term studies are needed to confirm the impact of prolonged tibolone or raloxifene administration on mammography.