Hormone replacement therapy, C-reactive protein, and fibrinogen in healthy postmenopausal women

Objective: To investigate short-term and long-term effects of combined hormone replacement therapy (HRT) on C-reactive protein (CRP) and fibrinogen plasma concentrations in healthy postmenopausal women. Methods: In this cross-sectional study 241 healthy postmenopausal women were enrolled. A total of 81 women were receiving the following treatments for 3 months; transdermal 17β-estradiol (17β-E₂)+medroxyprogesterone acetate (MPA) (n=21), oral 17β-E₂+norethisterone acetate (NETA) (n=27), and conjugated equine estrogens (CEE)+MPA (n=33). The same combined therapies were implemented in another 58 women for 12 months; transdermal 17β-E₂+MPA (n=10), oral 17β-E₂+NETA (n=16), and CEE+MPA (n=32). Control group included 102 healthy postmenopausal women not receiving HRT. The effect of the type and the duration of HRT regimens on plasma levels of CRP, fibrinogen and lipids were investigated. Results: Median CRP concentrations were significantly higher in women receiving oral 17β-E₂+NETA (P=0.037) and CEE+MPA (P=0.0001) for 3 months than in women taking the same types of HRT for 12 months and of those were not on HRT. Median CRP levels were similar in women taking transdermal 17β-E₂+MPA for 3 and 12 months, compared with controls. Fibrinogen levels were not different between nonusers and any group of HRT users. Conclusions: These elevated levels of CRP, which appears very recently as a crucial marker for cardiovascular disease, may be responsible for the early increased cardiovascular risk after starting oral combined HRT. But this increased risk in the early period seems to decrease with long-term use. Transdermal 17β-E₂+MPA had insignificant effect on CRP both in short-term or in long-term use.     

The values of urinary NTx in postmenopausal women undergoing HRT; the role of additional alendronate therapy

Objective: To determine the changes in levels of urinary NTx at the end of the 6th month of oral and transdermal hormone replacement therapy (HRT) and the effects of additional alendronate therapy for osteoporotic women. Method: Of 66 postmenopausal women 23 were treated with oral estradiol+norethisterone acetate (E+P), and 22 were treated with transdermal estradiol+norethisterone acetate. The third group consisted of 21 women with osteoporosis (bone mineral density<100 mg/cm³) and treated with oral E+P plus alendronate 10 mg/day. Result: Significant decreases of urinary NTx levels were seen after HRT in all study groups (P<0.05). But the decline of NTx levels was not different between the oral and transdermal HRT groups (P>0.05). There was no additional decrease in the levels of NTx with alendronate therapy (P>0.05) but NTx excretion diminished more in patients with high baseline levels. Conclusion: The decline of NTx at the end of the 6th month of HRT reflects the decrease of bone resorption and it is not related to the route of administration.     

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.     

Effects of hormone replacement therapy on postmenopausal uterine myoma

OBJECTIVES: To evaluate the effects of sequential continuous hormone replacement therapy (HRT) on myoma size and on pulsatility index (PI) of uterine arteries and to verify the correlation between uterine artery flow impedance and the growth rate of myoma in women receiving HRT. METHODS: In a prospective 1-year study 60 postmenopausal women were enrolled into three study-groups to receive continuous transdermal 17beta-oestradiol 0.05 mg/day plus nomegestrolo acetate 5 mg/day sequentially added: 20 patients (group A) unaffected by uterine myomas, 20 patients (group B) with single asymptomatic myoma <3 cm/14 cm3, 20 patients (group C) with single asymptomatic myoma >3 cm/14 cm3. The changes in myoma volume and in PI were assessed by means of transvaginal ultrasonographic scan every 3 months. The patients with myoma were divided into two subgroups: quiescent myoma (B1, C1) and growing myoma (B2, C2). RESULTS: No significant increase of uterine fibroids volume was found after 1-year HRT (24.14+/-20.02-->28.81+/-30.02 cm3). Six out of eight myomas growing during HRT belonged to group C. The uterine artery basal PI value of group A was significantly higher (P<0.01) than the corresponding PI in group B and C. At 3 months follow-up, uterine artery PI was significantly higher (P<0.01) than the basal value in both group B (1.70+/-0.22-->1.88+/-0.16) and C (1.59+/-0.28-->1.92+/-0.21). The baseline PI values in group B1 and C1 were significantly higher than the baseline values observed in group B2 and C2 (1.76+/-0.17 vs. 1.32+/-0.02, 1.76+/-0.16 vs. 1.24+/-0.08) and significantly lower than those observed in group A (2.39+/-0.47). After 3 months of HRT, the PI values were not significantly higher than the baseline values in groups B1 and C2 (1.76+/-0.17-->1.90+/-0.17; 1.24+/-0.08-->1.74+/-0.16), while they were significantly higher in group C1 (1.76+/-0.16-->2.01+/-0.17). CONCLUSIONS: Sequential continuous HRT does not increase the volume of the uterine myoma. The findings of very low resistance index in the uterine arteries of women with growing myoma may indicate the risk of growth of the neoplasia during HRT. The assessment of PI in the uterine arteries could be helpful in predicting the growth rate of the myomas before starting HRT.     

Longterm effects of hormone replacement therapy on symptoms of angina pectoris, quality of life and compliance in women with coronary artery disease

Objectives: The aim of the present study was to evaluate the effects of HRT on symptoms of angina pectoris, quality of life and factors of importance for compliance in women with ischemic heart disease. Methods: Sixty postmenopausal women with coronary artery disease were randomized into three groups: one group received transdermal 17β-estradiol at a dose 50 μg per 24 h alone for 18 days followed by 10 days of combined treatment with medroxyprogesterone acetate (MPA) 5 mg orally; the second group received placebo and the third group received conjugated estrogens orally for 18 days followed by a combined treatment with MPA for 10 days. Clinical evaluations were performed at baseline, after 3, 6 and 12 months. The investigations included gynecological history, occurrence of climacteric symptoms, quality of life evaluation, cardiac history and symptoms of angina pectoris. Results: Forty-six women (77%) completed the study during 1 year. The following cardiac events occurred in the women who completed the study: one patient was hospitalized because of congestive heart failure (patch), two patients because of angina pectoris, one patient because of coronary bypass operation (CEE) and three patients underwent balloon dilatation (placebo), all three on CEE. Among the 14 women who discontinued, two patients had TIA (patch), one experienced palpitations (CEE) and one woman died from myocardial infarction (placebo). Overall improvement in mood and cognitive functions were reported in all three treatment groups. Conclusions: HRT does not seem to have negative effects on symptoms of angina pectoris and seems to increase quality of life in older women with coronary heart disease. It also seems safe from the cardiovascular point of view.     

Low dose transdermal estradiol/norethisterone acetate treatment over 2 years does not cause endometrial proliferation in postmenopausal women

OBJECTIVE: We investigated the effects of 2-year transdermal continuous combined estradiol (0.025 mg/day) and norethisterone acetate (0.125 mg/day) (Estragest TTS) on bleeding and on the endometrium. DESIGN: This double-blind, randomized, multicenter, parallel, 1-year trial enrolled 266 healthy women at least 2 years past menopause with intact uteri. Patients received a transdermal patch delivering either 0.025 mg estradiol and 0.125 mg norethisterone acetate daily or placebo. Of the 266 women initially included, 135 (96 Estragest TTS, 39 placebo) completed a second year open follow-up, where all women had the estradiol/norethisterone patch. Endometrial biopsies were performed at weeks 0, 48 (n = 171), and 96 (n =109). Effects on endometrial morphology and uterine bleeding were studied. RESULTS: The overall incidence of endometrial hyperplasia after treatment with the estradiol/norethisterone acetate patch for one year was 0.8% with only one case of atypical hyperplasia. There were no clinically significant changes in endometrial thickness in either treatment group. The proportion of bleed-free patients with the estradiol/norethisterone acetate transdermal system increased from 55% in cycles 1-3 to 83% in cycles 10-12. By the 12th cycle, 92% of patients receiving estradiol/norethisterone acetate patches were bleed-free. No additional hyperplasia was seen during the second year follow-up. CONCLUSIONS: A continuous combined transdermal patch delivering 0.025 mg estradiol/day and 0.125 mg norethisterone acetate/day provided good endometrial protection. The dose maintained a consistently high rate of amenorrhea in postmenopausal women.     

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.     

National differences in lipid response to postmenopausal hormone replacement therapy

Objective: To compare the response of serum lipids and lipoproteins to the transdermal hormone replacement therapy (HRT) in five European countries. Methods: Five-hundred and sixty-seven healthy postmenopausal women from Belgium, Finland, the Netherlands, Sweden, and the UK received transdermal estradiol 50 μg daily for 12 months. In addition, two groups received transdermally norethisterone acetate (NETA) continuously, two groups sequentially (170 or 350 μg/day); one group received sequentially oral NETA (1 mg/day), and one group dydrogestrone (20 mg/day). Serum total cholesterol, HDL-, HDL2-, LDL-cholesterol, lipoprotein(a) (Lp(a)), and triglycerides were assessed before and at the end of treatment. Results: No significant national differences existed in the pretreatment levels of lipids and lipoproteins. Mean cholesterol, LDL, Lp(a), and triglycerides decreased during HRT, and HDL and HDL2 increased. Individual changes in responses to HRT were strongly dependent on pretreatment values. In this regard, British women differed from the others: their cholesterol, HDL, HDL2, and Lp(a) responses, when related to the pretreatment levels, were smaller than those of the others. Conclusion: A national difference discovered in response of serum lipids to HRT calls for caution in generalization of lipid data from one nation to another during HRT.     

Modification of serum IGF-I,IGFBPs and SHBG levels by different HRT regimens

During the menopause, levels of SHBG, IGF-I and IGFBPs are significantly modified by the use of different HRT regimens. Objective: The aim of this study is to evaluate the influence of three different HRT regimens on serum levels of SHBG, IGF-I, IGFBP-1 and IGFBP-3 in postmenopausal women. Methods: 41 postmenopausal women requesting HRT were enrolled in the study. Subjects were divided in three groups according to the therapy assigned; Group A: estradiol 2 mg/day+cyproterone acetate 1 mg/day in a cyclic sequential regimen; Group B: estradiol hemihydrate 2 mg/day plus norethisterone acetate (NETA) 1 mg/day in a continuous combined regimen; Group C: estradiol hemihydrate 1 mg/day plus NETA 0.5 mg/day in a continuous combined regimen. Blood samples were drawn before the start of hormonal treatment and after 6 months of HRT. Levels of SHBG, IGF-I, IGFBP-1 and IGFBP-3 in the serum were measured by means of a specific immunoassay. Results: In group A, a significant increase of SHBG, no change of IGFBPs and a significant decrease of IGF-I were observed; in group B and in group C, no significant variations for any of the parameters were recorded. Conclusions: The association of cyproterone acetate to oral estradiol determines a significant reduction of IGF-I levels and an increase of SHBG; nevertheless, it does not seem to influence the serum levels of the IGF-I binding proteins. The treatment with oral continuous combined estrogens plus androgenic progestins, at low doses, produces minor, not significant, changes in the circulating levels of IGF-I, SHBG and IGFBPs.     

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.     

Lipids and clotting factors during low dose transdermal estradiol/norethisterone use

OBJECTIVE: To demonstrate the effects of 2-year transdermal continuous combined low-dose estradiol (0.025 mg/day) and norethisterone acetate (0.125 mg/day) on lipid/lipoprotein profile and coagulation/fibrinolysis. METHODS: A double-blind, randomized, multicenter, parallel, 1-year trial enrolled 266 healthy women at least 2 years post menopause. Patients received either 0.025 mg estradiol and 0.125 mg norethisterone acetate daily or placebo transdermally. One hundred and thirty five women completed a second year open follow-up (96 had used Estragest TTS, 39 placebo during the first year), where all women had the estradiol/norethisterone patch. Lipid/lipoprotein profile and coagulation/fibrinolysis parameters were studied at 0, 24, 48, 72 and 96 weeks. RESULTS: In women on estradiol/norethisterone total cholesterol, Lp(a) and VLDL cholesterol decreased significantly more than in the placebo group after 24 weeks and LDL cholesterol after 48 weeks. Women on estradiol/norethisterone had no change in HDL, triglycerides or Lp(a), an increased HDL/total cholesterol ratio and decreased LDL, VLDL and total cholesterol at 48 weeks compared to placebo. Women with active treatment also showed a significant reduction compared with the placebo group of Factor VII and antithrombin III at 24 and 48 weeks and a reduction of fibrinogen at 24 weeks. These changes persisted over the second year. CONCLUSIONS: A continuous combined low-dose transdermal patch daily delivering 0.025 mg estradiol and 0.125 mg norethisterone acetate provided beneficial effects on lipid/lipoprotein profile and coagulation/fibrinolysis. The changes were similar to those previously described after higher dose oral and transdermal estrogen/progestogen regimens.     

Effects of low dose hormone replacement therapy on markers of inflammation in postmenopausal women

OBJECTIVE: Concentrations of soluble fractions of cell adhaesion molecules [sCAM], C-reactive protein (CRP) and serum amyloid A (SAA) are predictive for future cardiovascular events in postmenopausal women. The effect of hormone replacement therapy (HRT) on these inflammatory markers is not uniform. In the presented study the effect of a low-dose HRT preparation, on sCAM, CRP and SAA in healthy postmenopausal women was evaluated. METHODS: Serum levels of intracellular adhesion molecules (sICAM-1), vascular cell adhesion molecules (sVCAM-1), P-selectin, CRP and SAA were measured at baseline and after 12 weeks of treatment with continuous combined HRT containing 1 mg micronized 17beta-estradiol and 0.5 mg norethisterone acetate. The concentrations of total cholesterol, triglycerides LDL-cholesterol and HDL-c were measured as well. RESULTS: The studied low dose continuous combined therapy significantly reduced the concentration of sICAM-1, sVCAM-1 and P-selectin by 25.3, 20 and 34%, respectively. Despite statistically not significant the concentration of CRP and SAA increased by 35.6 and 9.4%, respectively. A statistically significant decrease in the triglycerides and TC/HDL-cholesterol ratio has been found. CONCLUSIONS: The outcomes of the presented study suggest that HRT with low dose continuous combined HRT containing 1 mg micronized 17beta-estradiol and 0.5 mg norethisterone acetate have divergent effects on studied parameters of vascular inflammation. These effects are similar to effects of other studied HRT combinations. To our best knowledge this is the first study evaluating the effect of HRT on the concentration of SAA.     

The effect of HRT on cerebral haemodynamics and cerebral vasomotor reactivity in post-menopausal women

BACKGROUND: Cerebral vasomotor reactivity (CVR) is an index of cerebrovascular dilatory capacity which can readily be assessed using trans-cranial Doppler ultrasound. Impaired CVR is associated with elevated risk of stroke. We performed a randomized, double-blind placebo-controlled trial to investigate the effect of two HRT preparations upon CVR. METHODS: We examined middle cerebral artery mean flow velocity (MFV), internal carotid artery pulsatility index (PI) and CVR to an i.v. acetazolamide bolus using ultrasound in three groups of post-menopausal women randomized to oral estradiol 1 mg+norethisterone 0.5 mg (group N), estradiol 1 mg+dydrogesterone 5 mg (group D) or placebo (group P). The MFV, PI and CVR were measured before and after 3 months treatment. RESULTS: Thirty-eight post-menopausal women were recruited (N=12, D=14, P=12); mean (SE) age was 56.7 (4) years. Neither HRT preparation affected CVR [% (SE) change from baseline N +4.2 (11); D +3.8 (5.5); P +4.0 (3.8); all comparisons P = NS]. PI was significantly reduced in recipients of dydrogesterone [% (SE) change from baseline D -5.4% (4.6); N +12.3 (6.9); P +11.6 (6.9). P=0.025]. Middle cerebral artery velocity was significantly increased following dydrogesterone treatment compared with placebo [% (SE) change from baseline D +6.8 (3.4) N +3.9 (4.2) P -4.6% (3.4) P=0.03 for D versus P]. CONCLUSION: HRT did not alter CVR. The reduced PI and increased MFV suggest HRT-induced intracranial vasodilatation, which is more apparent in dydrogesterone recipients. Differences may exist between progestogens with regard to changes in intracranial haemodynamics.     

HRT as secondary prevention of cardiovascular disease

Objective: To review the evidence of the efficacy of postmenopausal hormone replacement therapy (HRT) in secondary prevention of coronary artery disease or stroke. Results: Although a number of rather large and prolonged non-randomized observational studies have produced convincing and consistent evidence of the efficacy of HRT in the prevention of recurrence of cardiac events, the first randomized, placebo controlled trial (RCT) on heart disease and estrogen replacement study (HERS) reported no benefit of conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA) in secondary prevention of cardiac events in women with established coronary artery disease. This was supported by RCT reporting no effect of CEE or CEE + MPA on the progress of coronary sclerosis. Similarly, some nonrandomized observational studies have evaluated the risk of recurrent stroke in regard to the use of HRT, and the data are conflicting reporting a reduced or increased risk of recurrence for HRT users. One RCT has shown that low-dose estrogen treatment can only slow down the progression of carotid arteriosclerosis in high-risk postmenopausal women, whereas two other RCTs have shown no benefit (or risk) of using HRT for secondary prevention of ischemic stroke or progression of carotid atherosclerosis. Conclusion: The evidence accumutaed so far shows that HRT has no place in secondary prevention of coronary or carotic artery disease. Its use in these patients must be based on solid nonvascular indications and expected benefits from these causes.     

Effective bleeding control and symptom relief by lower dose regimens of continuous combined hormone replacement therapy: A randomized comparative dose-ranging study

Objectives: We compared two different continuous combined hormone replacement therapy (HRT) regimens of estradiol valerate (E₂V) and medroxyprogesterone acetate (MPA) with a combination of micronized estradiol (E₂) and norethisterone acetate (NETA) to determine bleeding pattern, control of climacteric symptoms, lipid profile, endometrial and general safety in a 1-year multicenter study. Methods: 440 postmenopausal women were randomized to three treatment groups to receive: 1 mg E₂V+2.5 mg MPA; 1 mg E₂V+5 mg MPA; or 2 mg of E₂+1 mg NETA. After the first 6 months, the E₂V dose was increased to 2 mg in both E₂V/MPA groups. Information on bleeding was recorded on diaries by the women and intensity of climacteric symptoms was assessed using VAS scales. Physical and laboratory examinations, endometrial biopsy and vaginal ultrasonography were performed at baseline and follow-up visits. Results: Significantly fewer bleeding days were experienced in the first 3 months by women taking E₂V/MPA compared with women taking E₂/NETA. When the dose of E₂V was increased in the E₂V/MPA groups, an increase in maximum bleeding intensity was observed in the group receiving 2.5 mg of MPA, but not in the group taking 5 mg of MPA. All dose combinations effectively relieved climacteric symptoms and beneficial effects on the lipid profile were seen after 6 months in all groups. Tolerability and endometrial safety were good and no cases of hyperplasia were observed. More women discontinued treatment prematurely in the E₂/NETA group compared with either of the E₂V/MPA groups. The overall continuation rates ranged from 70 to 86%. Conclusions: These results confirm that lower dose combinations of continuous combined HRT are usually sufficient to control symptoms or avoid breakthrough bleeding. However, if higher E₂V dose is needed for symptom control, it should be combined with the higher dose of progestin (5 mg) to avoid bleeding disturbances. Flexible treatment regimens should be available for individualized 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.     

Blood flow in the internal carotid and middle cerebral arteries: effects of continuous oral conjugated equine estrogens administration with monthly progestogen supplementation on postmenopausal women.

OBJECTIVE: This study was designed in order to evaluate the effect of conjugated equine estrogens (CEE) on internal carotid and middle cerebral artery blood flow in postmenopausal women. DESIGN: Thirty-four healthy postmenopausal women with intact uteri were randomly divided into two groups of 17 subjects each. The first group was treated for 24 weeks with continuous CEE medication (0.625 mg daily) and cyclical supplementations of 5 mg/day of medrogestone acetate, given on the last 12 days of every 4-week period (Prempak, Wyeth, Italy). The second group received no treatment. The pulsatility indices (PI) of both the internal carotid artery and middle cerebral artery were measured. RESULTS: In the treated group, the PI of the interior carotid artery and MCA was reduced from respectively 0.736 (0.016) and 0.745 (0.009) at baseline, to 0.669 (0.021) and 0.670 (0.011) after 24 weeks (p = 0.01); in the control group, the PI values remained unchanged. The between-group difference for both arteries was significant (p < 0.01). CONCLUSIONS: The administration of CEE with cyclical medrogestone supplementation to postmenopausal women induces a statistically significant reduction in the PI of cerebral arteries.     

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.     

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.     

Comparison of the effects of tibolone and estrogen replacement therapy on echocardiographic basic cardiac functions in post-menopausal women: a randomized placebo controlled study

Objectives: This study is designed to investigate and compare the effects of synthetic steroid tibolone and HRT on systolic and diastolic heart functions in post-menopausal women. Methods: This prospective, randomized placebo controlled double blind study was conducted in a university clinic. Fifty-eight non-smoking, otherwise healthy post-menopausal women who did not receive any kind of HRT at least for 3 years within the onset of menopause were included in the study. The patients were randomly allocated to either 2.5 mg per day tibolone (OD, n=18), daily combined 0.625 mg of conjugated estrogens 2.5 mg⁻¹ of medroxy progesterone acetate pill (EP, n=20) or a vitamin pill (n=20) in a double blinded fashion. Their basic systolic and diastolic functions were investigated with HP Sonos-1000 echocardiography using standard positions and windows before and 6 months after the initiation of HRT. Results: Mean age, weight, length of post-menopausal period, heart rate, systolic and diastolic pressures were similar between the groups. At the initiation of the study all groups had similar echocardiographic measurements. However, at the end of 6 months, left ventricular end-systolic and -diastolic volumes were decreased significantly compared to pretreatment and placebo in both EP and OD treated groups. (55.5±18.4 and 53.7±19.1.8 ml; 109.9±19.9 and 110.7±20.8 ml versus 74.5±14.9 and 142.7±19.1 ml, respectively; P<0.05). Improvement in diastolic functions was significant in EP/OD groups compared to pre-treatment period and the placebo groups (E/A 1.34±0.1 and 1.38±0.1 versus 1.18±0.09, deceleration time 204±11.1 and 202.8±27.1 ms versus 237.6±26.9 ms, respectively). Besides increase in left ventricular mass adjusted for height, decrease in left ventricular relative wall thickness, and systemic vascular resistance were significant in EP and OD treated groups than placebo and the pre-treatment measurements. Although improved in both OD and EP groups, the changes in systolic and diastolic functions were significantly higher in the OD treated group. Based on our preliminary results, we may conclude that both EP and OD regimens may improve cardiac performance and age related dysfunctions. Conclusion: The present results may further support that both OD and EP exert many direct effects on cardiovascular system other than metabolic changes regarding lipoproteins. The greater improvement in the OD group may be explained by its weak androgenic activity which is consistent with the in vitro data that androgens are potent relaxing agents on coronary arteries and restores cardiac myosin isoenzyme and ATPase patterns which mandates further clinical studies.