A comparative study of the effect of continuous combined conjugated equine estrogen plus medroxyprogesterone acetate and tibolone on blood coagulability

BACKGROUND: Hormone therapy (HT) after the menopause is associated with increased risk of venous thromboembolism (VTE). Tibolone has pharmacodynamic properties different from other hormone preparations. We compared the effect of a combined HT and tibolone on the inhibition of haemostasis. METHODS: Thirty-eight post-menopausal women were randomly assigned to 1.25 or 2.5 mg per day of tibolone or oral continuous combined conjugated equine estrogen plus medroxyprogesterone acetate (CEE/MPA). Inhibitors of haemostasis were measured at baseline and after 12 months. RESULTS: Results from the two groups of women receiving tibolone were not significantly different and, to improve the power of the study, the two groups were merged. Higher concentration of protein S (1.16 versus 1.00 IU ml(-1); P = 0.005) and higher activated protein C resistance ratio (APC-R) (4.2 versus 3.65; P = 0.04) were observed in the tibolone group than in the CEE/MPA group. Both doses of tibolone increased APC-R significantly (P < 0.01). Tissue factor pathway inhibitor (TFPI) was lower in the CEE/MPA group than in the tibolone group (67.8 versus 79.9 ng ml(-1); P = 0.03). CEE/MPA reduced the concentration of antithrombin (P = 0.002), protein S (P < 0.001) and TFPI (P < 0.001). Both preparations reduced the concentration of plasminogen activator inhibitor 1 (P < 0.05). CONCLUSIONS: Tibolone induces fewer pharmacological alterations on blood coagulability than CEE/MPA and has a potentially favourable effect on APC-R. This may translate into a corresponding low risk of VTE, as also indicated from the existing clinical data.     

Effects of estrogen, raloxifene, and hormone replacement therapy on serum C-reactive protein and homocysteine levels

OBJECTIVES: To investigate the effects of conjugated equine estrogen (CEE), CEE plus medroxyprogesterone acetate (MPA), CEE plus Nomegestrol acetate (NA), and raloxifene on serum high sensitivity C-reactive protein (hs-CRP) and homocysteine (Hcy) levels in healthy postmenopausal women. MATERIALS: One hundred seven healthy postmenopausal women were recruited in a prospective, randomized, and placebo-controlled 6 months study. Of these, 18 were hysterectomized and received daily oral 0.625 mg CEE. Eighty nine non-hysterectomized women were randomly allocated to one of four groups: a group (22 patients) treated with CEE, 0.625 mg/daily plus MPA 2.5 mg/daily; a group (22 patients) treated with CEE, 0.625 mg/daily plus NA 5 mg/daily; a group (23 patients) treated with raloxifene hydrochloride, 60 mg once daily; and a placebo group (22 patients). Hcy and hs-CRP were measured at baseline and at 3 and 6 months. RESULTS: CEE (20%, P=0.03) and CEE+MPA (59%, P=0.006) increased serum hs-CRP levels significantly, whereas CEE+NA decreased serum hs-CRP by 25% (P=0.01). Raloxifene had no significant effect on serum hs-CRP levels during and after the treatment. In all active treatment groups serum Hcy levels decreased significantly compared to baseline and placebo. CONCLUSIONS: Conjugated equine estrogen, hormone replacement therapies, and raloxifene lower serum Hcy levels to a comparable extent in postmenopausal women. Hs-CRP, as a cardiovascular risk factor, is not influenced by raloxifene, whereas CEE and CEE plus MPA significantly increase hs-CRP levels. Treatment with CEE plus NA reduces serum hs-CRP levels.     

The effect of hormone therapy on plasma homocysteine levels: a randomized clinical trial

OBJECTIVE: An elevated plasma homocysteine level is a risk factor for cardiovascular diseases. Hormone therapy (HT) may reduce fasting plasma homocysteine levels. We studied 80 postmenopausal women to determine the effect of medroxyprogesterone acetate (MPA) combined with conjugated equine estrogens (CEE) on fasting plasma homocysteine levels. DESIGN: In a randomized, double blind, prospective, placebo-controlled study, we randomly assigned 80 healthy postmenopausal women between CEE 0.625 mg/d combined with MPA 2.5 mg/d (n = 20), CEE 0.625 mg/d combined with MPA 5 mg/d (n = 20), unopposed CEE 0.625 mg/d (n = 20), and placebo (n = 20) all given for a duration of 6 months. Fasting plasma homocysteine levels were measured before and at the end of the treatment. RESULTS: Before treatment, plasma homocysteine concentrations were similar in all groups. After 6 months of unopposed CEE, the mean fasting plasma homocysteine levels decreased by 19.02% when compared with baseline levels (P < 0.05). The mean fasting plasma homocysteine concentrations decreased by 17.63% and 19.56% from baseline in both the CEE plus MPA 2.5 mg/d and CEE plus MPA 5 mg/d groups, respectively (P < 0.05 for each group). In contrast, plasma homocysteine levels increased by 11.66% in the placebo group. The homocysteine lowering effect did not differ significantly among the three groups of women receiving unopposed CEE alone and CEE plus MPA at two different doses. CONCLUSION: Six months of estrogen therapy (ET) and combined estrogen-progestogen therapy (EPT) significantly lower fasting plasma homocysteine levels in healthy postmenopausal women with equal efficacy.     

The effects of 17 beta-oestradiol plus dydrogesterone compared with conjugated equine oestrogens plus medroxyprogesterone acetate on lipids, apolipoproteins and lipoprotein(a)

OBJECTIVE: To compare the effects of 17 beta-oestradiol plus dydrogesterone with conjugated equine oestrogens plus medroxyprogesterone acetate on serum lipids, apolipoproteins and lipoprotein(a) in postmenopausal women. METHODS: A multi-centre, prospective, randomised, double-blind, comparative one-year study in 362 healthy postmenopausal women aged 39-74 years with an intact uterus. Fasting blood samples were taken at baseline and after 28 and 52 weeks of treatment. Participants received daily oral treatment with continuous combined 1 mg micronised 17 beta-oestradiol/5 mg dydrogesterone (E/D: n=180) or 0.625 mg conjugated equine oestrogens/5 mg medroxyprogesterone acetate (CEE/MPA: n=182). RESULTS: Significant differences between the two groups after 52 weeks were observed for total cholesterol (E/D: -1.7%; CEE/MPA: -7.3%), LDL-cholesterol (E/D: -4.5%; CEE/MPA: -11.3%), HDL-cholesterol (E/D: +15.3%; CEE/MPA: +7.5%), triglycerides (E/D: +9.8%; CEE/MPA: +16.6%), VLDL-triglycerides (E/D: -3.3%; CEE/MPA: +10.0%), lipoprotein(a) (E/D: 0.0%; CEE/MPA: -25.2%) and for the ratio apolipoprotein B/LDL-cholesterol (E/D: +0.9%; CEE/MPA +5.9%). CONCLUSIONS: E/D and CEE/MPA differ in their anti-atherogenic effects on lipids and lipoproteins. This however can not easily be translated to differences in clinical cardiovascular outcomes.     

Effects of four different regimens of hormone replacement therapy on hemostatic parameters: a prospective randomized study

OBJECTIVE: To compare the effects of four different regimens including oral and transdermal formulations with or without progestins on the hemostatic system in a prospective randomized fashion. METHODS: Eighty-eight women were randomized to four groups receiving continuous transdermal estradiol 50 microg/day (tE2), oral conjugated equine estrogen 0.625 mg/day (CEE 0.625 mg), oral conjugated equine estrogen 0.625 mg/day plus medroxyprogesterone acetate 2.5 mg/day (CEE 0.625 mg/MPA 2.5 mg), or oral 2 mg 17-beta estradiol combined with 1 mg norethistrone acetate (E2/norethistrone). The hysterectomized patients received only estrogen, and the remaining women received the estrogen plus progesterone combination regimens. As a marker of hemostatic system fibrinogen, tissue plasminogen activator (tPA), and plasminogen activator inhibitor-1 (PAI-1) levels were measured initially, and after 1 and 6 months of therapy. RESULTS: The treatment groups were well matched for baseline characteristics including age, height, weight, body mass index, and systolic and diastolic blood pressures. During the study period fibrinogen levels were below the baseline values in all groups. However, the decrease was only statistically significant in patients treated with oral 0.625 mg/day CEE. tPA levels were decreased significantly by tE2, CEE 0.625 mg, and CEE 0.625 mg/MPA 2.5 mg. PAI-1 levels were decreased significantly by CEE 0.625 mg, and CEE 0.625 mg/MPA 2.5 mg. When the effects of the four different regimens were compared using percentage changes from the baseline, no significant difference was found among the treatment groups. CONCLUSION: One of the treatment regimens resulted in a more coagulable state. Oral therapy with CEE decreased the levels of all parameters, and MPA did not impair this beneficial effect, except for in fibrinogen. Transdermal therapy had a minimal effect. No significant difference was noted among the four regimens.     

Prevention of postmenopausal bone loss with minimal uterine bleeding using low dose continuous estrogen/progestin therapy: a 2-year prospective study

Objective: To re-examine the minimal effective dose of conjugated estrogen (CEE)-progestin hormone replacement on postmenopausal bone loss. Design: A 2-year, prospective, open label, randomized study. Setting: Department of Obstetrics and Gynecology of a university hospital. Participants: Fifty-two postmenopausal or oophorectomized women. Intervention: One of the following regimens was continuously administered for 2 years: (1) CEE 0.625 mg/day, (2) CEE 0.625 mg + medroxyprogesterone (MPA) 2.5 mg/day, (3) CEE 0.31 mg + MPA 2.5 mg/day and (4) control. Measurements: Lumbar spine and femoral BMD by dual energy X-ray absorptiometry (DXA), a monthly based incidence of bleeding, serum lipids, PTH, calcitonin, Al-p, and osteocalcin. Results: Of the 52 patients enrolled in this study, 49 patients completed the 1 year of therapy and 36 completed the 2- year study. The control group showed a significant decrease in lumbar BMD over the 2 years (P < 0.05). The % changes in lumbar BMD at 2 years of CEE alone, CEE 0.625 + MPA and CEE 0.31 + MPA were 8.52% (95% confidence intervals; 4.61 ∼ 12.4%), 7.4% (0.60 ∼ 14.2%) and 3.20% (0.61 ∼ 5.84%), respectively, and were significantly higher than pretreatment values. The incidence of bleeding was significantly lower in women taking CEE 0.31 mg + MPA. HDL cholesterol increased in women taking CEE 0.625 mg alone or with MPA. No significant changes in lipid profiles were seen in the control or in the group of women taking CEE 0.31 mg + MPA. Conclusions: Continuous hormone replacement therapy (HRT) using 0.31 mg of CEE and 2.5 mg of MPA is effective in increasing lumbar BMD in postmenopausal or oophorectomized women and can be an appropriate option for women with a normal lipid profile or those women wishing to eliminate unscheduled bleeding.     

Impact on postmenopausal symptoms of adding continuous C-21 versus C-19 progestin to estrogen

OBJECTIVE: To compare the effects of (i) continuous low dosage C-19 progestin (dl-norgestrel, NG) plus cyclical conjugated estrogen (CEE) versus (ii) continuous low dosage C-21 progestin [medroxyprogesterone acetate (MPA)] plus CEE on postmenopausal vaginal bleeding, mood and somatic, psychosomatic and psychological symptoms. METHODS: Nine hypercholesterolemic postmenopausal women with intact uteri were randomly assigned in a prospective, double-blind, two-period cross-over study of CEE (25/28 days) plus either (i) NG, (0.05 mg/day) or (ii) MPA (2.5 mg/day) for 1 year and after an appropriate wash-out period were switched to the alternative regimen for another year. Four hysterectomized control subjects received the CEE only. RESULTS: Administration of CEE + MPA versus CEE + NG resulted in a significantly higher percent of cycles which were free of vaginal bleeding (97 vs 85%), spotting (92 vs 79%) and either spotting or bleeding (92 vs 76%, P < 0.01). All three regimens significantly reduced the overall combined scores for postmenopausal somatic, psychosomatic and psychological symptoms (P < 0.05). CONCLUSIONS: Vaginal bleeding and/or spotting were significantly less frequent with CEE + MPA versus CEE + NG. However, each of the three hormonal regimens improved mood and significantly reduced postmenopausal symptoms in comparison to untreated control values.     

Effects of two continuous hormone therapy regimens on C-reactive protein and homocysteine

OBJECTIVE: To compare the effects of two continuous hormone therapy (HT) regimens on the cardiovascular risk markers, C-reactive protein (CRP) and homocysteine. DESIGN: A prospective study in which 43 postmenopausal women were randomly assigned to either tibolone 2.5 mg/day (n = 20) or 0.625 mg/day conjugated equine estrogens (CEE) plus continuous medroxyprogesterone acetate (MPA) 5 mg/day (n = 23). Serum levels of CRP, homocysteine, vitamin B12, and folate were determined before and during 12 weeks of therapy. RESULTS: C-reactive protein levels were increased by tibolone (76%; P < 0.001) and CEE+MPA (81%; P < 0.001). Neither tibolone nor CEE+MPA had any significant effect on homocysteine levels, but there was a significant difference between the effects of treatment over time (P = 0.046). Both tibolone and CEE+MPA reduced vitamin B12 levels (11%; P < 0.001, and 8%; P < 0.01, respectively), but had no statistically significant effect on folate levels. Individual changes in homocysteine levels were negatively associated with changes in vitamin B12 levels (r = -0.68; P < 0.01) after tibolone therapy. CONCLUSION: Both tibolone and CEE plus MPA increased CRP levels and reduced levels of vitamin B12. Neither therapy had any significant effect on homocysteine levels. Further long-term studies into the effect of HRT on these markers, and the relationship to cardiovascular disease risk, are required.     

Effects of tibolone and conventional hormone replacement therapies on arterial and hepatic cholesterol accumulation and on circulating endothelin-1, vascular cell adhesion molecule-1, and E-selectin in surgically menopausal monkeys

OBJECTIVE: Menopause and aging are associated with a marked increase in the incidence of coronary heart disease as well as reductions in circulating estrogen, progestogen, and androgen levels. The synthetic compound tibolone and its metabolites have estrogenic, progestogenic, and androgenic characteristics. In the present study, we compared the effects of tibolone, estrogen replacement therapy, and estrogen plus progestogen replacement therapy on arterial and hepatic lipid accumulation and on circulating soluble adhesion molecule and endothelin-1 concentrations in surgically postmenopausal cynomolgus monkeys. DESIGN: Animals were fed an atherogenic diet for 2 years while receiving either no hormone treatment (control, n = 31) or the following treatments at doses designed to mimic the human dose on a daily caloric intake basis: tibolone at 2.5 mg/day (HiTib, n = 31), tibolone at 0.625 mg/day (LoTib, n = 29), conjugated equine estrogens (CEE) alone at 0.625 mg/day (CEE, n = 29), or CEE plus continuous medroxyprogesterone acetate (MPA) at 2.5 mg MPA/day (CEE + MPA, n = 30). RESULTS: Relative to the control group, iliac artery total cholesterol content was not different in the HiTib, LoTib, and CEE + MPA groups but was significantly lower in the group receiving CEE only (P < 0.05). In contrast, hepatic free cholesterol content was reduced in all treatment groups [HiTib (P < 0.01), LoTib (P < 0.05), CEE (P < 0.01), and CEE + MPA (P < 0.05)], whereas hepatic total and esterified cholesterol content were reduced in the HiTib, CEE, and CEE + MPA groups (all P < 0.05). HiTib and CEE groups had lower hepatic triglyceride levels per milligram of protein (P < 0.05). Iliac arterial cholesterol content was highly correlated with hepatic cholesterol content and with previously published histomorphometrically determined coronary artery atherosclerosis, supporting the use of the iliac artery as a surrogate for the coronary artery in the monkey. Circulating levels of soluble vascular cell adhesion molecule-1 were significantly reduced in the HiTib (P < 0.02) and CEE (P < 0.05) groups, whereas soluble E-selectin was reduced in the CEE group only (P < 0.01). Plasma endothelin-1 was significantly reduced in the LoTib (P < 0.05), CEE (P < 0.01), and CEE + MPA (P < 0.01) groups. CONCLUSIONS: These results suggest that while tibolone caused marked depression of high-density lipoprotein cholesterol and a resultant twofold increase in the total plasma cholesterol/high-density lipoprotein cholesterol ratio, those effects did not result in exacerbation of iliac artery atherosclerosis, perhaps because of beneficial effects on vascular biology or hepatic metabolism.     

Combination therapy of low-dose medroxyprogesterone acetate and oral estrogen does not affect endothelial function in the forearms of postmenopausal women

OBJECTIVE: We investigated whether low-dose medroxyprogesterone acetate (MPA) combined with oral estrogen had adverse effects on endothelial function compared with oral estrogen alone in postmenopausal women with mild hypercholesterolemia. DESIGN: Subjects were divided into two groups. One group received conjugated equine estrogen (CEE, 0.625 mg daily) orally for the first 3 months, followed by estrogen combined with MPA (2.5 mg daily) orally for an additional 3 months ( = 26). The other group received no treatment (control group, = 12). Forearm blood flow (FBF) during reactive hyperemia and after sublingual nitroglycerin administration was measured by strain-gauge plethysmography. Nitrite/nitrate, angiotensin-converting enzyme, and lipid concentrations were measured in the serum. RESULTS: Both CEE and CEE combined with MPA significantly increased the FBF during reactive hyperemia. This increase was similar in both active treatment phases. No changes were seen in controls. FBF after sublingual nitroglycerin did not change over 6 months in either group. Significant and similar increases in serum concentration of nitrite/nitrate and plasma renin activity as well as decreases in angiotensin-converting enzyme activity were found in both treatment phases. No such changes occurred in the control group. There was no significant increase in high-density lipoprotein cholesterol or decrease in low-density lipoprotein cholesterol between the treatment phases. Likewise, no such changes were observed in the control group. CONCLUSIONS: Our 6-month study suggests that the addition of low-dose MPA with CEE had no adverse effects on forearm resistance artery endothelial function compared with CEE alone.     

Quality of life assessment in a chemoprevention trial: fenretinide and oral or transdermal HRT

BACKGROUND: Oral conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA) relief menopause symptoms, but may increase breast cancer risk, while the effects of transdermal estradiol (E2) and MPA are less known. In previous studies, fenretinide decreased second breast malignancies in premenopausal but not in postmenopausal women, suggesting a hormone-sensitizing effect. We have evaluated the quality of life through a self-administered questionnaire during a randomized study of oral CEE or transdermal E2 and fenretinide or placebo. METHODS: A total of 226 postmenopausal women were randomly assigned to either CEE 0.625mg/day and placebo (n=55), or CEE and fenretinide 100mg/bid (n=56), or E2, 50microg/day and placebo (n=59), or E2 and fenretinide (n=56) for 12 months. Sequential MPA 10mg/day was added in all groups. Treatment effects were investigated using a validated questionnaire, the Menopause Quality of Life questionnaire (MENQOL). RESULTS: Oral CEE and transdermal E2 have a comparable activity in reducing menopausal symptoms (p=ns). Both routes ameliorate significantly the symptoms after 1 year of treatment (p<0.0001). Fenretinide does not modify the effects of hormonal replacement therapy. CONCLUSIONS: Oral CEE and transdermal E2 have similar effect on menopausal symptoms relief. The choice of the best estrogen replacement therapy (ERT) route should be decided based on a careful analysis of all the clinical aspects of every subject, considering that transdermal therapy may have a safer effect on the cardiovascular system.     

Conjugated estrogen plus medroxyprogesterone does not impair blood rheological properties in hypertensive postmenopausal women

OBJECTIVES: Hypertension and estrogens are both prothrombotic. We used the microchannel method to investigate whether hormone replacement therapy (HRT) with conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA) affects blood flow through the microchannels in hypertensive postmenopausal women being treated with antihypertensive drugs and in normotensive postmenopausal women. METHODS: Sixty-two consecutive postmenopausal women were randomly assigned to a hypertensive HRT group (n=16), hypertensive control group (n=15), normotensive HRT group (n=16) and normotensive control group (n=15). Each HRT group received CEE 0.625 mg plus MPA 2.5 mg daily orally for 12 months. Both hypertensive groups were being treated with antihypertensive drugs before the study. Microvascular blood flow was assessed on the basis of blood passage time, the time required for 100 microl of whole blood to pass through a cylinder, was determined before and 12 months after the start of HRT by the microchannel method (micro channel array flow analyzer). RESULTS: CEE plus MPA therapy did not change blood passage time in any of the groups. Microscopic observation showed that the whole blood passed smoothly through the microchannels in every group. CONCLUSIONS: CEE plus MPA therapy may not impair blood flow through the microchannels in hypertensive postmenopausal women receiving antihypertensive drugs or in normotensive postmenopausal women. However, administration of CEE plus MPA to postmenopausal women with hypertension warrants caution against the occurrence of thromboembolic events.     

New evidence regarding hormone replacement therapies is urgently required transdermal postmenopausal hormone therapy differs from oral hormone therapy in risks and benefits

Controversies about the safety of different postmenopausal hormone therapies (HTs) started 30 years ago and reached a peak in 2003 after the publication of the results from the Women Health Initiative (WHI) trial and the Million Women Study (MWS) [Writing group for the women's health initiative investigations. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002;288:321-33; Million women study collaborators. Breast cancer and hormone-replacement therapy in the million women study. Lancet 2003;362:419-27]. The single HT formulation used in the WHI trial for non hysterectomized women-an association of oral conjugated equine estrogens (CEE-0.625 mg/day) and a synthetic progestin, medroxyprogesterone acetate (MPA-2.5 mg/day)-increases the risks of venous thromboembolism, cardiovascular disease, stroke and breast cancer. The MWS, an observational study, showed an increased breast cancer risk in users of estrogens combined with either medroxyprogesterone acetate (MPA), norethisterone, or norgestrel. It is unclear and questionable to what extent these results might be extrapolated to other HRT regimens, that differ in their doses, compositions and administration routes, and that were not assessed in the WHI trial and the MWS. Significant results were achieved with the publication of the WHI estrogen-only arm study [Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 2004;291:1701-1712] in which hormone therapy was reserved to women who had carried out hysterectomy. What emerged from this study will allow us to have some important argument to develop.