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

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

Anticardiolipin antibodies during hormone replacement therapy in healthy postmenopausal women

Objective: The aim of the study was to investigate IgG and IgM anticardiolipin (aCL) antibodies in the course of hormone replacement therapy (HRT).

Subjects and methods: Thirty clinically healthy postmenopausal women with no history of previous thrombotic events or autoimmune disease were divided in two groups: control group (n=12, mean age 52.9±4.5 years, and 6.2±3.6 years duration of amenorrhea) and a second group (n=18, mean age 53.6±3.5 years, and 5.7±4.5 years of amenorrhea) who were allocated to HRT, containing 2 mg 17-beta estradiol plus 1 mg norethisterone acetate daily for 6 months. ACL antibodies of IgG and IgM isotype were assessed using ELISA and the Kupperman menopausal index (KI) was calculated at baseline and after 3 and 6 months of treatment. Results: HRT had a beneficial effect on climacteric symptoms, evaluated by KI (baseline versus 3rd month and 3rd month versus 6th month, P<0.001). The KI did not change in the control group. The values of IgG at the three studied periods did not change significantly and were 14.1±4.2, 13.1±4.9 and 13.4±3.7 in the HRT group and 12.7±3.1, 13.7±1.8 and 13.1±3.8 GPL, respectively, in the control group. IgM aCL antibodies increased during HRT and were as follows: 7.7±4.8 at baseline, 12.9±5.6 at 3rd month and 9.3±3.2 MPL at 6th month. In the control group, IgM were 8.0±2.8; 7.9±2.3 and 7.1±2.3 MPL, respectively. The differences between the two groups were significant at the third and the 6th month (P<0.01 and P<0.05). Conclusion: These data suggest that HRT is associated with elevation of IgM ACA in healthy postmenopausal women. As IgG aACA are considered more pathogenic, it seems unlikely that the early prothrombogenic effects of HRT can be assigned to ACA.     

Effects of bezafibrate and simvastatin on plasma lipoproteins in hypercholesterolemia resistant to hormone replacement therapy

Objectives: Estrogen replacement therapy has favorable effects on serum lipoprotein levels in postmenopausal women with hypercholesterolemia. However, there are some patients who fail to respond to hormone replacement therapy (HRT) to lower the serum cholesterol level. In these cases, a conventional lipid-lowering therapy will be applied in addition to HRT, while the effects of these drugs are not well understood. In this study, we studied the effects of simvastatin and bezafibrate administered in addition to HRT. Methods: Patients who were hypercholesterolemic even after HRT were randomly assigned to three treatment groups: HRT only (control group, n=10), HRT+simvastatin (10 mg/day, n=10), or HRT+bezafibrate (400 mg/day, n=10). Serum lipids and lipoprotein levels were measured throughout 12 weeks. Results: The serum triglyceride levels were decreased by 24±28 and 38±13% in the HRT+simvastatin and HRT+bezafibrate groups, respectively. HRT+simvastatin decreased the total cholesterol (21±10%) and low-density lipoprotein cholesterol (28±12%) levels without affecting the high-density lipoprotein cholesterol (HDL-C) level, while HRT+bezafibrate increased the HDL-C level (12±11%). Conclusions: Treatment with simvastatin or bezafibrate in addition to HRT should be considered in cases of postmenopausal hypercholesterolemia in which HRT alone fails to lower the serum lipoprotein levels.     

Comparison of transdermal estradiol and tibolone for the treatment of oophorectomized women with deep residual endometriosis

Study objective: To compare the effect of HRT with transdermal estradiol and that of treatment with tibolone in post-menopausal women with residual endometriosis. Materials and Methods: 21 women with residual pelvic endometriosis after bilateral oophorectomy with or without hysterectomy were enrolled in the study and were randomized to HRT with transdermal estradiol 50 mg twice weekly (n=10) associated with cyclic medroxyprogesterone acetate 10 mg daily in women who preserved uterus, and to treatment with tibolone 2.5 mg administered orally once a day (n=11). The duration of both treatments was scheduled to last at least 12 months. Residual endometriosis was located in the bowel wall in four patients, in the rectovaginal septum in six and deeply in the retroperitoneal pelvic space in six. All women were symptomatic before oophorectomy. Results: All the women were followed for 12 months. No patient suspended therapy because of side effects. Four patients of the estradiol group experienced moderate pelvic pain during treatment compared with only one patient in the tibolone group. One patient in the estradiol group reported severe dyspareunia. Conclusion: Although our series is very small, it seems that tibolone may be a safe hormonal treatment for post-menopausal women with residual endometriosis.     

Plasma leptin levels in obese and non-obese postmenopausal women before and after hormone replacement therapy

Objective: the aim of this study was to investigate the effect of hormone replacement therapy (HRT) on plasma leptin levels in postmenopausal women, and the relationship between the plasma leptin levels and obesity. Methods: premenopausal women with normal cycles (n=30; mean ages, 35.4±8.3 years) and postmenopausal women (n=45; mean ages, 49.5±4.7 years) were randomly selected. Women were classified as obese (BMI>27 kg/m²) and as non-obese (BMI<27 kg/m²). Blood samples were obtained from the premenopausal women at the beginning of cycle, and from the postmenopausal women before and 6 months after HRT. Plasma leptin levels were measured by radioimmunassay. Results: plasma leptin levels were significantly higher in premenopausal women than in postmenopausal women (18.60±5.0; 3.67±2.44 ng/ml, respectively, P<0.001). Obese premenopausal women (n=15) had significantly higher plasma leptin levels (24. 60±7.81 ng/ml) in comparison with the levels of the non-obese premenopausal women (n=15; 12.50±4. 63 ng/ml) (P<0.001). Although there was no significant difference in the plasma leptin levels between obese (n=25) and non-obese (n=20) postmenopausal women before HRT, plasma leptin levels were significantly elevated in both obese and non-obese postmenopausal women after HRT (P<0.001), and the obese women had significantly higher plasma leptin levels than the non-obese (29.05±10.53; 14.78±6.76 ng/ml, respectively, P<0.001). Conclusion: HRT is effective in the elevation of the plasma leptin levels in postmenopausal women, and in obese women the increase of the plasma leptin levels are more marked than the non-obese women after HRT.     

Effect of tibolone on breast symptoms resulting from postmenopausal hormone replacement therapy

Objective: To evaluate the incidence of breast symptoms in a population treated with various hormone replacement therapy (HRT) regimens and to detect the variations in breast symptomatology after HRT changing to tibolone administration. Methods: This prospective placebo-controlled clinical trial was conducted on healthy women on HRT reporting breast symptoms. A questionnaire was given to each woman to detect breast symptomatology. Breast tenderness and mastalgia were evaluated using a visual analogue scale (VAS). According to the choice of the each woman with breast symptoms, the HRT was changed to tibolone (2.5 mg/day per os) or to calcium carbonate (1 tab/day, placebo group). The duration of treatment was of 12 months. After 6 and 12 months breast symptomatology was re-evaluated. Results: Among the 600 screened women, 64 (10.7%) were suffering from breast symptomatology. After 6 and 12 months of treatment with tibolone or placebo, mean VAS score for breast tenderness and for mastalgia resulted significantly (P<0.05) decreased, without differences between groups, in comparison with basal value. Only one woman had no improvement from the breast symptoms with tibolone administration. Conclusions: Shifting from classical HRT to tibolone is followed by a significant reduction of breast symptomatology in postmenopausal women with breast complaints similar to that obtained with treatment withdrawal.     

Effect of menopause on low-density lipoprotein oxidation: is oestrogen an important determinant?

Objectives: Significantly increased risk for developing cardiovascular disease in post-menopausal women is linked with the fall of oestrogen. Although supraphysiological levels of oestrogen may inhibit oxygen free radical mediated low-density lipoprotein (LDL) oxidation, the effect of physiological level of oestrogen on LDL oxidation is unknown. Methods: The present study compared oxidizability of LDL in healthy pre- and post-menopausal women by using a commonly employed copper ion-dependent method. Results: Pre-menopausal women (n=20, mean age 27) had significantly higher serum oestradiol level (576±109 pmol/l) in comparison to post-menopausal women (n=23, mean age 51, oestradiol 64±18 pmol/l, P<0.001). The oxidation of LDL in two groups was not different by measuring either the lag phase of conjugated dienes formation (54±12 vs. 55±14 min, P>0.05) or the generation of thiobarbituric acid reactive substances over 4 h of oxidation. The major lipid soluble antioxidant in LDL, vitamin E (determined as -tocopherol) is similar in two groups (2.34±0.48 vs. 2.40±0.56 nmol/mg LDL, pre- and post-menopausal subjects, respectively, P>0.05). Linear regression analysis found a weak but significant correlation between LDL vitamin E level and oxidizability of LDL in both groups but did not show effect of serum oestradiol levels. Conclusion: The results suggest that physiological levels of oestrogen may not be able to affect in vitro LDL oxidation.     

The influence of physical activity on the response of bone mineral density to 5 years tibolone

Objectives: Menopausal hormone replacement therapy (HRT) maintains bone mineral density (BMD) and reduces risk of fracture in postmenopausal women. It has been suggested that sex steroids and loading may have synergistic effects on bone. We therefore investigated whether habitual physical activity influences the response of BMD to tibolone in postmenopausal women. Methods: The subjects were 42 postmenopausal women aged mean (SE) 65.8±6.2 year who had taken tibolone for prevention/ treatment of osteoporosis over 5 years. Bone mineral density was measured annually by dual X-ray absorptiometry and physical activity was assessed using accelerometers after 5 years therapy. Results: Twenty-six women were classified as having low physical activity (LPA; <15 min day⁻¹) and sixteen as high physical activity (HPA; >15 min day⁻¹). Spine BMD did not differ significantly between groups at baseline and increased significantly by 2 years of treatment with further increase to 5 years. The magnitude of increase did not differ between groups. Hip BMD at baseline was 7.3% higher in HPA women (P=0.07). Hip BMD increased over 2 years tibolone treatment in LPA women (+5.6%, P<0.01) whilst no significant change occurred in the HPA group (−0.5%). This difference in response between groups was statistically significant (P=0.002) and persisted after adjustment for age and body mass (P=0.002). Hip BMD was maintained in both groups over the subsequent 3 years of treatment. Conclusions: Spine BMD increased significantly in response to tibolone irrespective of physical activity participation. The more physically active women had higher hip BMD at baseline but the response to tibolone was greater in the less physically active women. The difference in response between groups may be due to physically active women having lower resorption at the hip and hence reduced response to anti-resorptive effects of HRT.     

Hormonal replacement therapy reduces forearm fracture incidence in recent postmenopausal women - results of the Danish Osteoporosis Prevention Study

Objectives: To study the fracture reducing potential of hormonal replacement therapy (HRT) in recent postmenopausal women in a primary preventive scenario. Methods: Prospective controlled comprehensive cohort trial: 2016 healthy women aged 45–58 years, from three to 24 months past last menstrual bleeding were recruited from a random sample of the background population. Mean age was 50.8±2.8 years, and the number of person years followed was 9335.3. There were two main study arms: a randomised arm (randomised to HRT; n=502, or not; n=504) and a non-randomised arm (on HRT; n=221, or not; n=789 by own choice). First line HRT was oral sequential oestradiol/norethisterone in women with intact uterus and oral continuous oestradiol in hysterectomised women. Results: After five years, a total of 156 fractures were sustained by 140 women. There were 51 forearm fractures in 51 women. By intention-to-treat analysis (n=2016), overall fracture risk was borderline statistically significantly reduced (RR=0.73, 95% CI: 0.50–1.05), and forearm fracture risk was significantly reduced (RR=0.45, 95% CI: 0.22–0.90) with HRT. Restricting the analysis to women who had adhered to their initial allocation of either HRT (n=395) or no HRT (n=977) showed a significant reduction in both the overall fracture risk (RR=0.61, 95% CI: 0.39–0.97) and the risk of forearm fractures (RR=0.24, 95% CI: 0.09–0.69). Compliance with HRT was 65% after five years. Conclusions: It is possible to reduce the number of forearm fractures and possibly the total number of fractures in recent postmenopausal women by use of HRT as primary prevention.     

Hormone replacement therapy improves arterial stiffness in normotensive postmenopausal women

Objectives: Aortic stiffness, determined by the pulse wave velocity (PWV), is an independent marker of cardiovascular risk. PWV is mainly influenced by age-associated alterations of arterial wall structure and blood pressure (BP). To determine the impact of hormone replacement therapy (HRT) on arterial compliance in normotensive, postmenopausal women, we examined the effects of HRT on PWV. Methods: Fifty-six postmenopausal women aged 50–70 years were recruited into the present retrospective study from the patients visiting our menopause clinic. Twenty-seven women who were prescribed HRT (14 on estrogen alone and 13 on estrogen plus progestogen) for several months to 6 years and an age-matched group of 29 women not on HRT were studied (Study 1). Nine postmenopausal women were also studied before and at 4 weeks of the treatment of estrogen replacement therapy (ERT) (Study 2). Brachial to ankle PWV (baPWV), which is correlated with aortic PWV, was determined using an automatic device, BP-203PRE. Results: In Study 1, PWV was significantly correlated with age in both groups (controls: r=0.392, P=0.035; HRT group: r=0.471, P=0.013), and HRT significantly lowered the PWV value at all ages examined (Mean±S.D. of baPWV in controls: 1382.2±114.1; HRT: 1245.3±124.8, P=0.0001). In Study 2, baPWV decreased significantly after ERT (P<0.05), without a significant change in systolic BP (P=0.851). Conclusions: Estrogen appears to improve arterial compliance independently of BP within 4 weeks.     

Vascular reactivity and atheromatous plaques in post-menopausal women on tibolone treatment. Open prospective study with Doppler ultrasonography in internal carotid artery

Background: Arteriosclerosis is the main cause of ischaemic ictus. The middle cerebral and anterior cerebral arteries, which irrigate over 70% of the entire cerebral tissue, spring from the internal carotid. Additionally, it is in the extracraneal vessels that embolism, thrombosis and stenosis originate more frequently. Aim: To evaluate the variations in blood flow (pulsatility index: PI) and to assess the evolution of atherogenic lesions (thickening of the vascular intima and the presence of atheromatous plaques) in the internal carotid artery after tibolone therapy. Subjects and methods: A total of 116 healthy menopausal women were included in this open, prospective and comparative study. Of them, 101 subjects completed the 48 weeks follow-up. Subjects were allocated in two groups: group T (n = 55) received 2.5 mg/day of tibolone daily and group C (n = 61) was a free-treatment control group. To evaluate both resistance to blood flow and the existence and evolution of atheromatous plaques in the internal carotid, an ultrasonograph with a pulsed Doppler was used. The PI was used as the parameter of vascular tone. To study atherosclerotic lesions in the internal carotid artery, we used morphological criteria. Measurements were done before entering in the study, and at 12, 24, 36 and 48 weeks of treatment. Results: After tibolone treatment the PI in the internal carotid artery was observed markedly diminished. Moreover, tibolone reduces both the thickness and length of atheromatous plaque and the degree of vascular stenosis. Conclusion: tibolone administration reduced the carotid atheromatous plaque in thickness and length and improved cerebral perfusion.     

Early effects of continuous low-dosage dl-norgestrel administered alone or with estrogen

Twenty-six postmenopausal women participated in a double-blind trial involving treatment according to a Latin square design with either (i) dl-norgestrel alone (0.075 mg/day) continuously for two cycles, (ii) estradiol-17β alone (1 mg on 25 of 28 days) for two cycles, or (iii) the combined hormones for six cycles. A placebo control cycle followed each hormonal treatment. Plasma triglycerides decreased by an average of 22% during treatment with either dl-norgestrel alone (123 ±11 vs. 160 ±10 mg/dl, n = 25, P < 0.005) or combination therapy (126 ±11 vs. 162 ±11, n = 25, P < 0.005) as compared with control. Plasma total cholesterol fell by 5% during two cycles of treatment with either dl-norgestrel alone (229 ±11 vs. 242 ±10 mg/dl, n = 25, P < 0.02) or combination therapy (233 ± 11 vs. 246 ±10, n = 25, P < 0.05) versus placebo. During the fifth and sixth cycles of combination therapy 94% of cycles were free of flushing (vs. 31% for control, P < 0.01), 64% of cycles were free of spotting not requiring protection (control 75%), 96% of cycles were free of vaginal bleeding (control 100%), endometrial biopsy showed inactive endometrium in nine of the 10 subjects re-biopsied, fasting blood pyruvate decreased by 20% (P < 0.05) and diastolic blood pressure fell by 4% compared with control (P < 0.05), whereas glucose tolerance was unchanged. There was a significant reduction in vasomotor flushing beginning with the third to fourth cycles of combination therapy.     

Effects of tibolone on body composition in postmenopausal women: a 1-year follow up study

Objective: We investigated the effects of 1-year tibolone treatment on body weight, body composition and indices of android obesity in postmenopausal women.

Methods: Forty-four postmenopausal women participated in this open-label controlled study; mean age was 51.8 ± 2.21 years and all women were menopausal for 3.8 ± 1.40 years. Twenty-two of them started taking 2.5 mg tibolone (TIB) daily for 1 year, whereas the remaining 22 served as age-matched controls. All subjects underwent a structured interview, physical examination, body composition measurements performed by dual-energy X-ray absorptiometry (DXA) — Hologic QDR 4500 A, as well as bioelectrical body impedance analysis (BI) — Tanita TBF-215, Japan.

Results: The TIB group did not significantly increase their weight (+0.4 kg), while the non-treated controls increased their mean weight by 1.4 kg (p = 0.046). In the TIB group, DXA showed a non-significant body fat decrease by a mean of 0.5 kg and a non-significant lean mass increase by 0.8 kg, while in the control group, fat mass increased by 1.7 kg (p = 0.032) and lean mass did not change. BI revealed that the TIB group had lost some fat (≈0.6 kg, n.s.) and put some free-fat mass (≈1.0 kg, p = 0.048) without changes in total body water. The control group put on some fat (≈1.1 kg, p = 0.042) and lost some body water (≈0.4 kg, n.s.).

Conclusion: Results from both methods of measuring body composition show a similar trend: a decrease in fat mass and an increase in lean mass in TIB treated subjects. From the body composition perspective, tibolone may be regarded as a preferential alternative to conventional hormonal therapy (HT) in postmenopausal women.     

Effect of HRT on hormone responses to resistance exercise in post-menopausal women

Purpose: The purpose of this study was to evaluate the effect of hormone replacement therapy (HRT) on the acute and chronic hormonal responses to resistance exercise in post-menopausal women. Methods: Thirty-two post-menopausal women were recruited for this study; 16 who were currently using HRT and 16 who were not using HRT. Subjects in both the HRT and NHRT groups were randomly assigned to either a resistance training group (N=16; 8 HRT and 8 NHRT) or a control group (N=16; 8 HRT and 8 NHRT). The training group completed a supervised resistance training program three times a week for 12 weeks. To evaluate changes in hormone levels, resting blood samples were drawn at weeks 0, 4, and 13 of the program. In addition, at weeks 0 and 13, post-exercise blood samples were drawn in order to examine the hormone response to an acute bout of resistance exercise. Samples were analyzed for serum growth hormone (GH), insulin-like growth factor-1 (IGF-1), testosterone, estradiol, dehydroepiandrosterone (DHEA), and cortisol. Results: There were no significant changes in resting hormone levels between weeks 0, 4, and 13 of the training program. There was a significant week-by-group interaction for DHEA (P<0.05) and cortisol (P<0.05) with the NHRT-training group having a greater post-exercise increase in DHEA and cortisol after training. Overall, the post-exercise GH levels were significantly greater than pre-exercise (P<0.05) or recovery levels (P<0.01). There were no significant differences between HRT and NHRT groups in the acute hormone response to exercise. Conclusion: These results indicate that HRT will not have an effect on the acute or chronic hormone response to a recreational resistance training program in post-menopausal women.     

Metabolic effects of tibolone in postmenopausal women with non-insulin dependent diabetes mellitus

Objective: Postmenopausal women with non-insulin dependent diabetes (NIDDM) are frequently obese, hypertensive and hyperlipidaemic and hence at particular risk of coronary heart disease (CHD). They might therefore benefit from menopausal therapy. In view of the improvement in insulin sensitivity and the reduction in triglyceride levels induced by tibolone in healthy postmenopausal women we evaluated the effects of 12 months of tibolone on glycaemic control, serum insulin and lipid levels in postmenopausal women with NIDDM. Design: A prospective 12 months before/after intervention study. Patients: Fourteen postmenopausal women (mean age 58.14±1.25 years; mean duration of menopause 121.21±13.42 months; mean BMI: 26.55±0.97) with NIDDM (mean duration of diabetes 113.79±13.89 months). Measurements: Fasting and postprandial blood glucose levels were assessed monthly, serum fructosamine, fasting and postprandial insulin every 3 months and serum lipids (total cholesterol, triglyceride, HDL-cholesterol and LDL-cholesterol) every 6 months. Results: Changes in blood glucose, both fasting and postprandial, were not statistically significant during the treatment period. Serum fructosamine concentration increased significantly after 9 months. A significant decrease in fasting and postprandial insulin concentrations was observed after 9 months. A non-significant decrease was observed in total cholesterol, LDL cholesterol and triglyceride but no change in HDL cholesterol. Body weight did not change during the period of observation. Conclusion: A slight deterioration in glycaemic control, a fall in insulin concentration and no change in serum lipids were observed in women with NIDDM during 12 months treatment with tibolone.     

Early impact of hormone replacement therapy on vascular hemodynamics detected via ocular colour Doppler analysis

Objective: To determine the effects of hormone replacement therapy (HRT) on ocular blood flow.

Study design: In a prospective controlled study, 40 healthy women who presented to the menopause clinic between December 2000 and December 2001 were randomly assigned into the study. The HRT-receiving group was administered estradiol 17-valerate 2 mg the first 11 days, and estradiol 17-valerate 2 mg plus ciproterone acetate 1 mg the next 10 days of the monthly cycle for 6 months. The control group did not receive any HRT for 6 months. The ocular colour Doppler analysis were performed at baseline and after 3 and 6 months. The ocular Doppler analysis was performed in the first half of the cycle in the HRT-receiving group.

Results: Central retinal artery and ophthalmic artery basal Doppler index (peak systolic velocity, end-diastolic velocity, resistive index and pulsatility index) values of the two groups at the beginning of the study did not show any statistically significant difference. Both the right and the left central retinal artery pulsatility index (PI) values of the study group, who received HRT at the end of the third and sixth months, showed a statistically significant decline (paired-samples test, P < 0.05), while the decrease in the resistive indexes was not significant.

Conclusion: These results suggest that 6 months of combined hormone replacement therapy with estradiol 17-valerate 2 mg plus ciproterone acetate 1 mg improves ocular vascular Doppler indices which may be a reflection of cerebral vascular status.     

Influence of hormonal replacement therapy on the regional cerebral blood flow in postmenopausal women

Objectives: The aim of this study was evaluation of the influence of hormonal replacement therapy (HRT) on the regional cerebral blood flow in postmenopausal women. Methods: The study group were 20 postmenopausal women, mean age 48.7 years (S.D. ±4.9 years). The control group were ten regularly menstruating women, mean age 32.6 years (S.D. ±13.2 years). In the studied group we measured the severity of climacteric syndrome with the use of Kupperman index and serum FSH and 17β-estradiol level with the use of radioimmunological method. Cerebral blood flow was measured at rest using Single Photon Emission Computed Tomography (SPECT). Tracer accumulation evaluation was performed in three slices defined as: cerebellar slice, thalamic slice and ventricular slice, the reference region was delineated in the cerebellum. In ten women with an impairment in the cerebral blood flow at the beginning of the study all the tests were repeated after 12 months of HRT. Results: Before HRT mean value of the Kupperman index in the study group was 29.8 points (S.D. ±7.1 points); 17β-estradiol 27 pg/ml (S.D. ±2 pg/ml); FSH 56 IU/l (S.D. ±49.5 IU/l); SPECT study revealed cerebral blood flow impairment in ten women. In all the studied slices cerebral blood flow was lower in the study group than in the controls. After 12 months of HRT the mean value of the Kupperman index in the study group was 13.2 points (S.D. ±2.1 points) (P<0.05); 17β-estradiol 44 pg/ml (S.D. ±25 pg/ml); FSH 36.4 IU/l (S.D. ±57.3 ng/ml); we found cerebral blood flow increase in all studied slices: right cerebellar slice: 5.2%; left cerebellar slice: 4.1%; right thalamic slice: 3.8%; left thalamic slice: 3.3%; right ventricular slice: 7.5%*; left ventricular slice: 6.7%* (* P<0.05). Conclusions: Cerebral blood flow is lower in the postmenopausal women than in regularly menstruating women. HRT increases regional cerebral blood flow and this improvement coexists with an increase of serum 17β-estradiol level.     

Do women using hormone replacement treatment have less pre-existing cardiovascular risk

Background: Several studies have suggested that women who choose to use hormone replacement therapy (HRT) already, before starting this therapy, have a better cardiovascular risk profile than those who do not use it. Some of these studies contain factors of confusion and biases, such as HRT users’ greater educational achievement or physical activity, which could have led to wrong conclusions. Aim: To study a cohort, without confounding factors in order to analyse whether the cardiovascular risk profile is different in women who choose to use HRT. Material and methods: Coronary risk factors of 387 women between 45 and 64 were studied. This study was carried out at the Unit for the Preventive Medical Examination of the South Metropolitan Health Service in Santiago (Chile) during the annual check-up. The first evaluation was in 1991–1992; with a second evaluation 5 years later. Of all the women, 174 (45%) never received hormones (Group A), 124 (32%) were HRT users at the time (Group B), and 89 (23%) were former-users (Group C). Results: No differences were found between the three groups for age, body mass index (BMI), educational background, alcohol consumption, smoking or physical activity. Blood pressure was similar in the three groups. No significant differences were found in total cholesterol (A, 221.7±42.2; B, 228.2±47.0; and C, 227.3±44.9 mg/dl); high density lipoprotein (HDL, A, 53.5±13.2; B, 51.8±12.8; and C, 54.0±12.4 mg/dl); low density lipoprotein (LDL, A, 141.7±38.9; B, 148.5±43.1 and C, 148.3±43.8 mg/dl); triglycerides (A, 134.5±67.9; B, 141.0±66.1; and C, 127.3±68.5 mg/dl) and glucose plasma levels (A, 90.5±32.2; B, 87.7±15.3; and C, 85.0±8.8 mg/dl). Conclusions: Our results suggest that women who choose to use HRT have a cardiovascular risk profile, before starting the therapy, similar to those who do not use it.     

Correlation of estrogen receptor beta gene polymorphisms with spinal bone mineral density in peri- and post-menopausal Greek women

Estrogens play a significant role in bone physiology. Their action is mainly exerted through their receptors. Estrogen receptor alpha (ER) plays a major role in bone homeostasis and there is evidence suggesting that estrogen receptor beta (ERβ) has also an effect on BMD.

We investigated the possible effect of two ERβ gene polymorphisms on spinal bone mineral density (BMD) and metabolic bone markers in Greek women.

Spine BMD as well as biochemical bone markers were measured in 147 healthy peri- and post-menopausal women [mean age (S.D.) 54 (7.9) years]. Genotyping was performed for two restriction fragment length polymorphisms (RFLPs) of ERβ gene, RsaI in exon 5 and AluI in exon 8. For each polymorphism studied the cohort was divided into two groups: the “wild-type” group (RR and AA, respectively) and the “carrier” group including subjects with at least one allele with the restriction site (Rr&rr and Aa&aa, respectively).

The distribution of RsaI genotypes was RR: 91.2% (n = 134), Rr: 8.2% (n = 12), and rr: 0.6% (n = 1) and of AluI genotypes AA: 36.7% (n = 54), Aa: 57.2% (n = 84), and aa: 6.1% (n = 9). No linkage disequilibrium was found between the two polymorphic sites studied. Spine BMD did not differ significantly in the two groups of either polymorphism, after adjusting for age, weight, height, and years since menopause [mean BMD (S.D.) for RR 0.841 (0.17) g/cm² versus Rr&rr 0.798 (0.13) g/cm², p = 0.25, and mean BMD (S.D.) for AA 0.828 (0.16) g/cm² versus Aa&aa 0.848 (0.17) g/cm², p = 0.32]. No significant differences were noted in metabolic bone markers except for a marginal difference of RR versus Rr/rr in urinary hydroxyproline/creatinine ratio [median (IQR) 3.88 (6.04) μmol/mmol in RR versus 8.2 (4.32) μmol/mmol in Rr/rr, p = 0.05]. Furthermore, no interaction between the two polymorphisms on BMD was found.

In conclusion, in a Greek female post-menopausal population, the two ERβ gene polymorphisms were not associated with BMD, or metabolic bone markers.     

Progestins used in hormonal replacement therapy display different effects in coronary arteries from New Zealand white rabbits

Objectives: The aim of this study was in an animal model to assess the vascular effects of different progestins commonly used in hormonal replacement treatment. Methods: Fifty-six non-atherosclerotic, ovariectomized New Zealand white rabbits were randomized into seven groups: (1) medroxyprogesterone acetate (MPA), (2) norethisterone acetate (NETA), (3) conjugated equine estrogens (CEE), (4) 17-β-estradiol (E2), (5) MPA+CEE, (6) NETA+E2, (7) or placebo (n=8) and given hormonal treatment through the diet for 4 weeks. Ring segments from the left proximal coronary artery and from the distal part of the left anterior descending coronary artery were microdissected and mounted for isometric tension recordings in a myograph. The vasoconstrictory responses induced by potassium, endothelin-1, calcium and N_w-nitro- -arginine methyl ester, and the vasodilatory response induced by acetylcholine and sodiumnitroprusside were investigated. The maximum contraction/relaxation (E_max) and the concentration required to induce half the maximum response (EC₅₀) were determined. EC₅₀ values were expressed as the negative logarithm to the molar concentration, pD₂=−log EC₅₀. Results: Treatment with MPA alone caused when compared to treatment with NETA an increase in tension development in the distal coronary artery after the addition of potassium (6.36±0.36 versus 4.31±0.42 P<0.005) (single dose response, mN/mm, mean±S.E.M.) and endothelin-1 (9.41±0.82 versus 6.43±0.73 P<0.05) (E_max, mN/mm, mean±S.E.M.). Treatment with MPA compared to placebo caused an endothelin-1 induced increase of E_max in the distal coronary artery (9.21±0.87 versus 6.51± 0.65 P<0.05) and a calcium induced increase of pD₂ in both coronary arteries (2.98±0.19 versus 2.42±0.12 P<0.05, proximal coronary artery) (3.26±0.09 versus 2.9±0.1 P<0.05, distal coronary artery) (pD₂, mean±S.E.M.). Treatment with NETA compared to placebo in the proximal coronary artery, after the addition of sodiumnitroprusside caused a decrease of pD₂ (5.33±0.19 versus 5.94±0.13 P<0.05). Treatment with E2 compared to treatment with CEE in the proximal coronary artery caused a decrease of pD₂ after the addition of sodiumnitroprusside (5.00±0.16 versus 5.77±0.28 P<0.05). No significant differences were found between MPA+CEE and NETA+E2. Conclusion: Treatment with MPA alone seems to enhance the contractile response to potassium and endothelin-1 in the distal coronary artery compared to NETA, indicating that different progestins used in hormonal replacement treatment may display different effects on contractile functions of coronary arteries.