Bleeding profile and endometrial safety of continuous combined regimens 1 mg 17beta-estradiol/trimegestone versus 1 or 2 mg 17beta-estradiol/norethisterone acetate in postmenopausal women.

OBJECTIVE: To compare the bleeding profile and endometrial safety of continuous combined 1 mg 17beta-estradiol (17beta-E2) and 0.125 mg trimegestone (TMG) with those of two continuous combined 17beta-E2 and norethisterone acetate (NETA) regimens. STUDY DESIGN: This was a double-blind, randomized, multicenter study conducted in 12 European countries and Israel over a 2-year period. Healthy postmenopausal women with an intact uterus were given either 1 mg 17beta-E2/0.125 mg TMG, 2 mg 17beta-E2/1 mg NETA or 1 mg 17beta-E2/0.5 mg NETA for up to 26 cycles, each of 28 days. RESULTS: The percentage of amenorrheic women was greater in most cycles up to cycle 13 in the 1 mg 17beta-E2/0.125 mg TMG group than in the comparator groups. The mean number of bleeding days was similar in the 1 mg 17beta-E2/0.125 mg TMG and the 1 mg 17beta-E2/0.5 mg NETA groups, but greater in the 2 mg 17beta-E2/1 mg NETA group. No endometrial hyperplasia was observed for any group. CONCLUSION: Continuous combined 1 mg 17beta-E2/0.125 mg TMG exhibits a more favorable bleeding profile than 1 mg 17beta-E2/0.5 mg NETA up to 1 year, while providing an adequate protective effect on the endometrium.     

A comparative 2-year study of the effects of sequential regimens of 1 mg 17beta-estradiol and trimegestone with a regimen containing estradiol valerate and norethisterone on the bleeding profile and endometrial safety in postmenopausal women.

OBJECTIVE: To compare the bleeding profiles and endometrial protection of two sequential regimens of 17beta-estradiol (17beta-E2) and trimegestone (TMG) with a sequential estradiol valerate (E2V)/norethisterone (NET) regimen. STUDY DESIGN: This was a randomized, double-blind, multicenter study conducted in eight countries in healthy, postmenopausal women with an intact uterus. A total of 1218 women were enrolled into the initial 1-year study (13 cycles), and subsequently 531 of these received treatment for a further year (26 cycles). Treatment regimens were 1 mg 17beta-E2 on days 1-14 and 1 mg 17beta-E2/0.125 mg TMG or 1 mg 17beta-E2/0.25 mg TMG on days 15-28, and 1 mg E2V on days 1-16 and 1 mg E2V/1 mg NET on days 17-28. RESULTS: Mean percentage of women reporting onset of withdrawal bleeding episodes during the week following discontinuation of progestogen was higher in the 1 mg 17beta-E2/0.25 mg TMG group than in the other two treatments, showing a more efficient progestogen effect on the endometrium and good predictability of bleeding onset with this treatment. The mean numbers and average lengths of bleeding episodes were similar in the three treatment groups. Overall, the bleeding profile was more favorable with 1 mg 17beta-E2/0.25 mg TMG than with the lower-dose TMG preparation. Both of the TMG regimens demonstrated a good protective effect on endometrial proliferation, with the 0.25 mg TMG dose showing a lower incidence of proliferative endometrium. CONCLUSION: The 1 mg 17beta-E2/0.25 mg TMG regimen showed an adequate protection of the endometrium, with an overall favorable bleeding profile.     

Efficacy on climacteric symptoms of a continuous combined regimen of 1 mg 17beta-estradiol and trimegestone versus two regimens combining 1 or 2 mg 17beta-estradiol and norethisterone acetate.

OBJECTIVES: To compare the efficacy of a continuous combined regimen of 1mg 17beta-estradiol (17beta-E2) and 0.125 mg trimegestone (TMG) with two continuous combined 17beta-E2/norethisterone acetate (NETA) combinations in the relief of climacteric symptoms in postmenopausal women. STUDY DESIGN: This was a randomized, double-blind, multicenter study conducted in 13 countries over a 2-year period. Healthy postmenopausal women with an intact uterus were treated with 1 mg 17beta-E2/0.125 mg TMG, 2 mg 17beta-E2/1 mg NETA or 1 mg 17beta-E2/0.5 mg NETA for up to 26 cycles, each of 28 days. RESULTS: The 1 mg 17beta-E2/0.125 mg TMG combination was effective in significantly reducing the mean daily number and severity of hot flushes and in reducing the number of night sweats from cycle 1 onward. No overall significant differences between this regimen and the comparators were detected. Other efficacy variables, including the Kupperman index, psychofunctional disorders and quality-of-life sub-scales, experienced a similar improvement from baseline with all treatments. CONCLUSION: Continuous combined 1 mg 17beta-E2/0.125 mg TMG provides relief of menopausal symptoms that is non-inferior to both 17beta-E2/NETA combinations. Furthermore, trimegestone appeared to provide a better improvement of depressive mood than 0.5 mg NETA when combined with 1 mg 17beta-estradiol.     

A study of the control of climacteric symptoms in postmenopausal women following sequential regimens of 1 mg 17beta-estradiol and trimegestone compared with a regimen containing 1 mg estradiol valerate and norethisterone over a two-year period.

OBJECTIVE: To compare the efficacy of two sequential 17beta-estradiol (17beta-E2)/trimegestone (TMG) combinations with the sequential estradiol valerate (E2V)/norethisterone (NET) regimen in relieving climacteric symptoms. STUDY DESIGN: This was a double-blind, randomized, multicenter study conducted among 1218 Caucasian (99%) postmenopausal women with an intact uterus in seven European countries and Israel, over 13 cycles (each of 28 days). Study duration was extended further for 13 cycles, with 531 women receiving treatment for up to 26 cycles. Treatments consisted of 1 mg 17beta-E2 on days 1-14 and 1 mg 17beta-E2/0.125 mg TMG or 0.25 mg TMG on days 15-28, and 1 mg E2V on days 1-16 and 1 mg E2V/1 mg NET on days 17-28. RESULTS: Rapid and significant reductions in the mean daily number and severity of hot flushes and in the mean daily number of nocturnal sweats were established in most women with 1 mg 17beta-E2/0.25 mg TMG and E2V/NET. These treatments also induced a significant improvement in the quality-of-life assessments. CONCLUSION: The 1 mg 17beta-E2/0.25 mg TMG regimen provides rapid and effective relief of menopausal symptoms, with a reduction in the number of hot flushes "at least as good as" that of the E2V/NET comparator.     

Effects of intranasal 17beta-estradiol and raloxifene on lipid profile and fibrinogen in hypercholesterolemic postmenopausal women: a randomized, placebo-controlled clinical trial.

AIM: To compare the effects of 17beta-estradiol given intranasally (intranasal E2) and raloxifene on serum lipid profile and fibrinogen in hypercholesterolemic postmenopausal women. METHODS: The study population consisted of 46 women after menopause. The placebo group (n = 11) was given calcium, while the intervention groups were given intranasal E2 (Aerodiol; Servier, Chambray-les-Tours, France) (n = 16) or raloxifene (Evista; Lilly SA, Madrid, Spain) (n = 19). Blood lipids and fibrinogen were compared between groups at baseline and after 3 months of treatment. RESULTS: The group receiving intranasal E2 showed a significant decrease in triglyceride levels (p<0.05) and a marked increase in high-density lipoprotein cholesterol levels (p<0.05). No changes in lipid profile were observed in the raloxifene and placebo groups. Raloxifene caused a significant decrease in fibrinogen levels (p<0.05). CONCLUSION: Intranasal E2 exerts significant effects on lipid profile in hypercholesterolemic postmenopausal women. Raloxifene has a greater impact on fibrinogen than intranasal E2 application.     

Effects of sequential combined transdermal and oral hormone replacement therapies on serum lipid and lipoproteins in postmenopausal women

The aim of this study was to compare the effects of sequential combined transdermal and oral postmenopausal hormone replacement therapies on serum lipid-lipoprotein profiles risk markers for cardiovascular disease. A prospective randomize study was designed: Ninety-six healthy nonhysterectomised postmenopausal women were randomized to receive either transdermal continuous 17β-estradiol, 0.05 mg/d (Estraderm TTS, Novartis, Basel, Switzerland), with transdermal sequential norethisterone acetate, 0.25 mg/d (Estragest TTS, Novartis, Basel, Switzerland), or oral continuous conjugated equine estrogens, 0.625 mg/d (Premarin 0.625 mg, Wyeth, Philadelphia, U.S.A.), with oral sequential medroxyprogesterone acetate, 10 mg/d (Farlutal 5 mg, Deva, Istanbul, Turkey). 84 women completed the trial, 42 in oral and 42 in the transdermal group. The serum levels of total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, apolipoproteins AI and apolipoproteins B at 6 months after starting treatment were compared with baseline values for both therapies. Both oral and transdermal therapies significantly reduced serum levels of total cholesterol (208– 190 mg/dL and 216–199 mg/dL, respectively, p=0.0001) and LDL-cholesterol (128–112 mg/dL and 140– 127 mg/dL, respectively, p=0.001). The serum levels of triglycerides did not show any significant change with oral therapy, whereas this lipid fell (128–101 mg/dL, p=0.0001) significantly with transdermal therapy. We found significant decrease in HDL-cholesterol with transdermal therapy while there was no significant change with oral therapy. Apolipoproteins AI, the major protein component of HDL₂ subfraction, was increased by oral therapy and lowered by transdermal therapy. As a conclusion, we have found that serum total cholesterol and LDL-cholesterol were lowered by both therapies, with no significant differences between treatments, whereas there were significant differences between treatments according to effects on serum triglycerides and apolipoproteins AI. Received: 15 May 2001 / Accepted: 20 July 2001     

Effect on endometrium of combined oestrogen-progestogen replacement therapy of 1 mg 17beta-estradiol and 0.5 mg norethisterone acetate

The purpose of the study was to determine the effects of low-dose hormone replacement therapy (HRT) on ultrasound thickness of the endometrium and on endometrial histology in postmenopausal women. Two hundred and fifty-four postmenopausal women were included in the study; 124 completed three years of treatment with continuous HRT containing 1 mg oestradiol and 0.5 mg norethisterone acetate daily, and 130 women did not take HRT during the same time (control group). Ultrasound scan showed that the mean thickness of the endometrium was similar between the groups under investigation at the end of the study. Ninety-one percent of the women in the HRT group and 78% in the control group had an atrophic or unassessable endometrium and no cases of endometrial hyperplasia or malignancy were detected in either group at endometrial biopsy at the end of the study. It seems that low-dose continuous HRT of moderate duration is not associated with either endometrial hyperplasia or malignancy.     

The long-term effects of low-dose 17beta-estradiol and dydrogesterone hormone replacement therapy on 24-h ambulatory blood pressure in hypertensive postmenopausal women: a 1-year randomized, prospective study.

OBJECTIVE: The aim of this study was to assess the long-term effects of low-dose oral hormone replacement therapy (HRT) on 24-h blood pressure in hypertensive postmenopausal women. STUDY DESIGN: In this 12-month, prospective study, 66 postmenopausal women with mild or moderate hypertension were randomly assigned to receive either HRT with 1 mg/day micronized 17beta-estradiol sequentially combined with 10 mg/day dydrogesterone for 14 days of each 28-day cycle, or no therapy. Ambulatory blood pressure measurements were recorded for a 24-h period at baseline and after 12 months of treatment or follow-up. RESULTS: Blood pressure did not differ significantly between the groups at baseline. After 12 months, there were falls in 24-h systolic, diastolic and mean arterial blood pressure in both the HRT and control groups; only the fall in mean arterial blood pressure in the HRT group achieved statistical significance (-2.0 +/- 0.8 mmHg, p < 0.01). While there was no significant decrease in daytime systolic or mean arterial blood pressure in either group, a significant decrease in diastolic blood pressure (-1.8 +/- 10 mmHg, p < 0.001) was observed in the HRT group. Night-time systolic and mean arterial blood pressure also decreased significantly (p < 0.001) in the HRT group (-3.0 +/- 1.5 mmHg and -2.2 +/- 0.6 mmHg, respectively), but no significant change was observed in the control group. Conclusion: Low-dose oral HRT caused significant falls in both daytime and night-time ambulatory blood pressure in postmenopausal women with mild or moderate hypertension.     

Effects of 15 months of 17 beta-estradiol and dydrogesterone on systolic cardiac function according to quantitative and Doppler echocardiography in healthy postmenopausal women

OBJECTIVE: Our goal was to investigate the short-term and intermediate effects of low-dose hormone replacement therapy on echocardiographic parameters of cardiac function in healthy postmenopausal women. STUDY DESIGN: In a prospective, controlled study 30 healthy postmenopausal women (mean age, 52 +/- 3 years) were randomly assigned to 2 groups. Women in the hormone replacement therapy group (n = 15) received 1 mg micronized 17 beta-estradiol daily sequentially combined with 5 or 10 mg dydrogesterone for 14 days of each 28-day cycle during 12 months and thereafter 2 mg 17 beta-estradiol combined with 10 mg dydrogesterone for a period of 3 months. The control group (n = 15) received no treatment. M-mode, quantitative 2-dimensional, and Doppler echocardiographic measurements were performed at baseline and within the 17 beta-estradiol phase at 3, 12, and 15 months. RESULTS: After 12 months significant differences in change between the 2 groups were found for left ventricular end-diastolic and left ventricular end-systolic diameters, left ventricular mass index, and stroke volume index. These differences were caused by changes in the control group rather than in the hormone replacement therapy group, in which no significant within-group changes were found. All other parameters measured showed no effect. CONCLUSION: Within 15 months of 17 beta-estradiol and dydrogesterone treatment no clinically relevant differences were found in the M-mode, quantitative 2-dimensional, and Doppler echocardiographic parameters measured in this study. It is suggested that 15 months of treatment probably is too short a period for detection of direct effects on the heart itself.     

Beneficial effects of low doses of ethinyl-estradiol on the lipid profile in postmenopausal women

The purpose of this study was to investigate the beneficial effects of low doses of ethinyl-estradiol on the lipid profile in postmenopausal women. One hundred and five patients (mean age [+/-S D] 42.9 +/- 5.0 years) who underwent a hysterectomy and bilateral salpingo-oophorectomy were included in the study. For the present study serum levels of total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, apolipoprotein B (apoB), and lipoprotein(a) [Lp(a)] were investigated. When all patients were considered together (Table 1), EE2 therapy significantly increased serum levels of total cholesterol, HDL cholesterol and LDL cholesterol. The ratio of HDL to LDL cholesterol, Lp(a) and triglyceride concentrations did not change significantly from the baseline value. Although our study was not randomized or controlled with a placebo, the beneficial metabolic effects of ethinyl-estradiol on lipid patterns should be considered in patients needing hormonal replacement therapy in postmenopause.     

Lipid effects of hormone replacement therapy with sequential transdermal 17-beta-estradiol and oral dydrogesterone

OBJECTIVE: To assess the effects on lipid and lipoprotein levels of a combination therapy of matrix patch and oral sequential dydrogesterone. METHODS: The lipid effects of transdermal estradiol (E2) (80 microg/day continuously) and oral dydrogesterone (10 mg from days 15-28 of each cycle) were assessed in a multicenter, prospective, open, baseline-controlled study. Subjects were 42 healthy, postmenopausal women who had not had hysterectomies. Fasting blood samples were taken at baseline, day 14 of cycle 3 (estrogen alone), and day 25 of cycle 6 (estrogen and progestogen). The main outcome measures were changes from baseline in total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides after six cycles. RESULTS: Thirty-six subjects completed six cycles and in the 28 with complete data, HDL cholesterol increased by 10.6% from 65.25 to 72.2 mg/dL (95% confidence interval [CI] 2.32, 11.58, P = .005) and LDL cholesterol fell by 5.1% from 130.9 to 124.3 mg/dL (95% CI 13.9, 1.16, P = .07). There was a nonsignificant decrease in LDL cholesterol from 130.9 at baseline to 124.3 mg/dL at 6 months and in triglycerides from 110.6 to 107.1 mg/dL. CONCLUSION: Sequential treatment with transdermal E2 and oral dydrogesterone increased HDL cholesterol, without the accompanying increase in triglycerides that occurs with oral estrogen replacement therapy.     

Greek-origin royal jelly improves the lipid profile of postmenopausal women

Aim: Menopause transition is associated with chronic conditions such as osteoporosis and cardiovascular disease. Concerns about the long-term safety of menopausal hormone therapy make alternative natural methods an appealing approach to management. The aim of this study was to examine the effect of royal jelly (RJ) on cardiovascular and bone turnover markers in clinically healthy postmenopausal women.

Methods: A total of 36 postmenopausal healthy women were studied in a prospective follow-up study. Participants received 150?mg of RJ daily for three months. Circulating cardiovascular risk markers [lipid profile, antithrombin-III (ATIII), Protein C, Protein S, Plasminogen Activator Inhibitor-1 (PAI-1)] and bone turnover parameters [Total calcium, phosphate (P), parathormone (PTH), total type-1 Procollagen N-terminal (P1NP), Osteocalcin and serum collagen type 1 cross-linked C-telopeptide (CTX)] were compared between the baseline and the three-month visit.

Results: The RJ used in this study was particularly rich in medium chain fatty acids, compounds with hypolipidemic properties, which comprised 63% of the dry weight fatty content. RJ treatment resulted in a significant increase in high density lipoprotein – cholesterol (HDL-C 60.2?mg/dL?±?12.3 versus 64.7?mg/dL?±?13.9, 7.7% increase, p?=?0.0003), as well as in a significant decrease in low density lipoprotein – cholesterol (LDL-C, 143.9?±?37.5 versus 136.2?±?32, 4.1% decrease, p?=?0.011) and in total cholesterol (224.4?±?38.6 to 216.1?±?36.5, 3.09% decrease, p?=?0.018). No statistical significant changes were found in the remaining cardiovascular or the bone turnover parameters.

Conclusions: The intake of RJ 150?mg for three months is associated with significant improvements of the lipid profile of postmenopausal women. RJ supplementation may offer an alternative method of controlling the menopause – associated dyslipidemia.     

Beneficial effects on serum lipoproteins by 17 beta-oestradiol-dydrogesterone therapy in postmenopausal women; a prospective study.

STUDY OBJECTIVE: To study the possible changes of reproductive hormones, sex hormone binding globulin, serum lipids and lipoproteins, lipoprotein (a) included, coagulation and glucose in postmenopausal women treated with 17 beta-oestradiol and cyclic dydrogesterone for 14 days per 28 days treatment cycle. DESIGN: Open longitudinal prospective study. DURATION: Twelve 28 days treatment cycles. SETTING: Gynaecological department of university hospital. SUBJECTS: 27 healthy postmenopausal women. RESULTS: After treatment for six cycles serum concentrations of FSH and LH decreased significantly with 43.0% and 24.4%, respectively. Serum concentrations of 17 beta-oestradiol and oestrone increased significantly with 302% and 792%, respectively, and SHBG increased as well with 111% (P < 0.01). Serum total cholesterol decreased with 9.0% (P < 0.01). Serum VLDL-cholesterol did not change significantly. Serum LDL-cholesterol decreased with 16.3% (P < 0.01) and HDL-cholesterol increased with 8.0% (P < 0.01). This was accompanied with similar significant changes in the apolipoproteins: apolipoprotein A-I rose with 14.4% and apolipoprotein B decreased with 6.0%. Serum triglycerides and VLDL-triglycerides increased significantly with 14.4% and 17.9%, respectively. Lipoprotein (a) decreased with 17.5% (P < 0.01). These results more or less sustained at cycle 12 of treatment. Serum concentrations of antithrombin III and glucose did not change. Fibrinogen decreased slightly but significantly below the initial value. CONCLUSIONS: This combination replacement therapy gives beneficial changes in lipid-metabolism, indicating a reduced risk of developing coronary heart disease without unfavourably changing coagulation and glucose metabolism. The expected beneficial changes with oestradiol alone are not counteracted by the intermittent addition of dydrogesterone. Therefore this oestrogen/progestagen scheme can, indeed, be recommended for use in HRT.     

Influence of a continuous combined HRT (2 mg estradiol valerate and 2 mg dienogest) on postmenopausal depression.

OBJECTIVE: This randomized, double-blind, placebo-controlled study was planned to investigate the effects of continuous combined hormone replacement therapy (HRT) with 2 mg estradiol valerate and 2 mg dienogest (Climodien/Lafamme) over 24 weeks on postmenopausal depression. METHOD: A total of 129 patients with a mild to moderate depressive episode according to ICD-10: F32.0, F32.1 in the context of a postmenopausal syndrome (ICD-10: N95.1) and a baseline score in the Hamilton depression scale (HAMD) > or =16 were included in the study. The primary target variable was depression severity as measured by the HAMD after 24 weeks of treatment. A four-point difference between HRT and placebo at the end of the study and, in addition, a final score < or =8 (corresponding to an improvement of > or =50% as compared to baseline) for the individual patient (responders analysis) were considered clinically relevant. Clinical global impression (CGI) of investigators (therapeutic and side-effects) at the end of the study was investigated. Secondary effects of HRT on depression severity caused by its effect on vasomotor symptoms or sleep disturbances (domino hypothesis) were taken into consideration. Also, the study addressed the question of whether the effect of HRT on depression severity depends on a history of premenstrual syndrome (PMS) or postnatal depression (PND). RESULTS: The results showed a clear and clinically relevant reduction of depression severity under HRT after 24 weeks of treatment and superiority over placebo (p < 0.0005) in spite of a strong placebo effect. The effects of the estrogen-progestin combination thereby seemed only partially to be dependent on the improvement of vasomotor symptoms and sleep disturbances. Also, the effects of HRT could not be shown to be dependent on a history of PMS and/or PND, even though women with and without this history clearly differed in baseline depression scores (p < 0.0001). The assessment of CGI was positive: whereas HRT was clearly superior to placebo with regard to therapeutic effects (p = 0.0014), there were no differences with regard to side-effects (p = 0.35). CONCLUSION: The combination of 2 mg estradiol valerate and 2 mg dienogest can be regarded as an effective and safe treatment option for women with mild to moderate depression in the context of postmenopausal syndrome.