Search

OBJECTIVE Currently, hormone replacement therapy is applied successfully to reduce post-menopausal bone resorption. However, the exact mechanism by which oestrogen exerts its effect has not yet been fully elucidated. In order to determine whether changes in the biologically active 1,25-dihydroxyvitamin D3 may be of importance in this process, the concentrations of both total and free 1,25-dihydroxyvitamin D3 in serum were assessed. DESIGN In 36 post-menopausal women the effect of hormone replacement therapy, with a combination of 17β-oestradiol and norethisterone acetate, on the serum levels of total and free 1,25-dihydroxyvitamin D3 was studied after 0, 3, 6 and 12 cycles. MEASUREMENTS The total concentration of 1,25-dihydroxyvitamin D3 in serum was assessed using a radioreceptor assay after diethylether extraction of the samples followed by paper chromatography. The free fraction of 1,25-dihydroxyvitamin D3 was measured using symmetric dialysis. The free 1,25 dihydroxyvitamin D3 concentration was calculated by multiplying the total concentration by the free fraction. RESULTS During therapy, mean serum total 1,25-dihydroxyvitamin D3 concentrations (± SD) were 106.4 pmol/l (± 27.5), 155.0 pmol/l (± 49.5), 176.7 pmol/l (± 70.0) and 161.1 pmol/l (± 55.3) at 0, 3, 6 and 12 cycles, respectively. Serum free 1,25-dihydroxyvitamin D3 concentrations were 68 fmol/l (± 22), 107 fmol/l (± 35), 120 fmol/l (± 43) and 108 fmol/l (± 37), respectively. Baseline values of both total and free 1,25-dihydroxyvitamin D3 were significantly lower than those during therapy at all time (P ≤ 0.001). CONCLUSION Both the serum total 1,25-dihydroxyvitamin D3 and the serum free 1,25-dihydroxyvitamin D3 concentrations are increased during combined 17β-oestradiol and norethisterone acetate therapy for a year. Assuming that the free concentration 1,25-dihydroxyvitamin D3 reflects the biologically active fraction, this rise may in part explain the preventive effect of hormone replacement therapy on osteoporosis.

This multicenter, randomized, parallel-group, open-label study was conducted to compare the effects of gestodene (GTD) 60 microg/ethinylestradiol (EE) 15 microg and desogestrel (DSG) 150 microg/EE 20 microg (Mercilon) on selected metabolic measurements during six cycles in 124 healthy women.GTD/EE subjects received a single pill once daily from days 1 to 24 of a 28-day cycle, followed by placebo pills daily for the last 4 days of the cycle. DSG/EE subjects received a single pill daily from days 1 to 21 of a 28-day cycle, followed by a 7-day pill-free interval. Safety was assessed from changes in hemostatic measurements, lipid profile, glucose tolerance and adverse events.Both GTD/EE and DSG/EE groups exhibited minimal effects on the lipid profile. An increased glucose response was noted with both treatments and an increased insulin response was noted with GTD/EE. Hemostatic activity was increased in both groups but a counteracting increase in fibrinolytic activity occurred together with an increase in coagulatory activity. The incidence of adverse events was comparable between groups, and no significant differences in cycle control were observed between groups. No pregnancies occurred in either group.The 24-day GTD 60 microg/EE 15 microg formulation and DSG/EE produced similar effects on hemostatic balance, lipid metabolism and glucose tolerance, and exhibited comparable efficacy and tolerability.

To investigate the effect of postmenopausal oral and transdermal hormone therapy on plasma levels of C-reactive protein (CRP), we performed a randomised, double-blind, double-dummy, placebo-controlled, 15-month study. One hundred and fifty-two healthy hysterectomised postmenopausal women received daily either placebo (n = 49), or transdermal 17beta-oestradiol (E(2)) 50 micro g (tE(2) group, n = 33), or oral E(2) 1 mg (oE(2) group, n = 37), or oral E(2) 1 mg combined with gestodene 25 micro g (oE(2) + G group, n = 33) for thirteen 28-day treatment cycles, followed by four cycles placebo for each group. Data were collected at baseline and in cycles 4, 13 and 17. In cycle 13, CRP was significantly increased in the oE(2) group compared to placebo (P = 0.004). The median percentage change from baseline versus placebo was +75% (P0.001). In cycle 17, significantly lower values were observed in the oE(2) group compared to cycle 13 and to the placebo group (-49%, P0.001). There were no significant changes versus placebo in the other groups. In conclusion, oral E(2) significantly increased CRP levels. This change was larger than the increase found during oral E(2) + G. Transdermal E(2) did not affect CRP levels.

Hormone replacement therapy (HRT) increases the risk of cardiovascular morbidity in postmenopausal women under certain circumstances. Part of this effect may be the result of the influence of HRT on blood platelets. We studied the effect of short-term oral hormone replacement therapy (unopposed oestradiol or sequentially combined oestradiol and trimegestone or dydrogesterone) on platelet activation parameters in healthy postmenopausal women.We designed a prospective, randomised, placebo-controlled 12-week study. Sixty healthy, normotensive, nonhysterectomised, postmenopausal women received daily micronised oestradiol (E2) 2 mg (n = 16), or 2 mg E2 daily sequentially combined with either trimegestone 0.5 mg daily (n = 14) or dydrogesterone 10 mg daily (n = 14), or placebo (n = 16). Data on platelet activation were collected at baseline and after 12 weeks of treatment using flow cytometry.Twelve weeks of treatment with combined HRT was associated with an increase in platelet activation parameters P-selectin and glycoprotein 53 (by 17% and 14%, respectively, P = 0.04 vs. the placebo group for both comparisons), suggesting alpha granule and lysosome degranulation. E2 replacement therapy was associated with an increase in P-selectin labelling by 22% (P = 0.04 vs. the placebo group).Short-term treatment with oestradiol or combined HRT increases the amount of circulating activated platelets as measured by flow cytometry. This could be a mechanism by which short-term HRT might increase the risk of thrombosis.

This randomized, double-blind, multicenter study was planned to compare the efficacy and tolerance of a novel oral regimen containing estradiol (2.0 mg) sequentially combined with trimegestone, at a daily dose of either 0.25 mg or 0.5 mg, with a standard hormone replacement therapy containing estradiol and norethisterone acetate (E2 + NETA) in the treatment of climacteric symptoms.The study was conducted over 13 cycles, each of 28 days, and involved 487 subjects, of whom 349 completed the study.All three treatments were equally effective in alleviating hot flushes and showed a progressive and significant reduction in the value of the Kupperman index. The treatments diminished equally effectively urogenital signs and symptoms. All treatments were well tolerated and the incidences of adverse events associated with each treatment were similar across the treatment groups. The duration of expected withdrawal bleeding was shorter in the estradiol + trimegestone 0.5 mg group than in the estradiol + trimegestone 0.25 mg or E2 + NETA group.All treatments were effective and well tolerated, providing significant relief from climacteric symptoms. Treatment with estradiol + trimegestone 0.5 mg provided the most favorable bleeding pattern.

To exclude pre-existing endometrial pathology in asymptomatic early post-menopausal women before starting hormone replacement therapy by transvaginal ultrasound (TVS) and saline infusion sonohysterography (SIS).In a cross-sectional study, 148 healthy women (mean age, 51.1 years; range, 46-59 years) underwent ultrasound evaluation of the endometrium before participation in a clinical trial. TVS was used to measure double-layer endometrial thickness. SIS was performed at the same visit to measure anterior and posterior single-layer endometrial thickness, and to identify endometrial abnormalities when present. Ultrasound results were defined as informative if the endometrium could be adequately visualized. Findings on TVSs were defined as abnormal if a double-layer endometrial measurement5.0 mm was obtained. Findings on SIS were defined as abnormal if one or both single layers of the endometrium measured2.5 mm, or if focal endometrial thickening or a polyp was present.Of the 148 eligible women, informative TVS results were obtained from 134 women, SIS results from 133 women and both procedures combined from 119 women. TVS scans gave abnormal results in 8.2% of women (11 of 134) and SIS gave abnormal results in 36.8% of women (49 of 133). Of the 14 women with a non-informative TVS, eight had abnormal SIS results. Of the 15 women with a non-informative SIS, three had abnormal TVS results. In the 119 women with both informative TVS and SIS, abnormal TVS scans were found in 6.7% of women (eight of 119) and abnormal SIS in 34.5% of women (41 of 119). All eight women with abnormal TVS had an abnormal SIS, whereas 29.7% (33 of 111) of the women with a normal TVS had an abnormal SIS.Ultrasound evaluation demonstrated endometrial abnormalities in 34.5% (41 of 119) of asymptomatic post-menopausal women. SIS is more accurate than TVS in the detection of endometrial abnormalities.

In this randomised, placebo-controlled 12-week study, sixty healthy postmenopausal women received either placebo (N = 16) or daily 2 mg micronised oestradiol, either unopposed (N = 16, E2 group) or combined with a progestagen for 14 days of each cycle (N = 28, E2+P group).As compared to placebo, plasma levels of AT III were reduced only in the E2 group (approximately 28%), plasma levels of protein C decreased only in the E2+P group (approximately 4%) and plasma levels of protein S decreased in both the E2 and E2+P group (approximately 21%). In both the E2 and E2+P groups, the plasma levels of factor VII (antigen and activity) showed a borderline significant increase (approximately 10%), whereas no significant change was observed in active factor VII. Plasma levels of tissue-type plasminogen activator (approximately 22%), urokinase plasminogen activator (approximately 25%) and plasminogen activator inhibitor type-1 (approximately 43%) decreased in the E2 and E2+P groups, whereas those of plasminogen increased (approximately 12%). Treatment was associated with an increase in levels of prothrombin fragment 1+2 (approximately 31%), but levels of thrombin-antithrombin III complexes, and of plasmin-alpha2-antiplasmin complexes and total fibrin(ogen) degradation products did not change significantly.Short-term E2 and E2+P treatment is associated with a shift in the procoagulant-anticoagulant balance towards a procoagulant state. A substantial proportion of women do not have a net increase in fibrinolytic activity. These data may be relevant in explaining the increased risk of venous thromboembolism associated with ERT and HRT, and possibly also in explaining the negative results of the Heart and Estrogen/progestin Replacement Study.

Epidemiological data have suggested that the use of hormone replacement therapy (HRT) is associated with a decreased risk of cardiovascular disease. Vascular endothelium and adhesion molecules play an important role in the initiation and progression of atherosclerosis.Prospective, randomized, placebo-controlled 12-week study. Sixty healthy, normotensive postmenopausal women received either micronised oestradiol 2 mg alone (n = 16, E2 group), or sequentially combined with a progestagen; E2 + P groups trimegestone 0.5 mg (E2 + T, n = 14) or dydrogesterone 10 mg (E2 + D group, n = 14) or placebo (n = 16). Data were collected at baseline and at 4 and 12 weeks.Twelve weeks of treatment with E2 or E2 + P was associated with a significant decrease in the plasma concentrations of soluble intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), and thrombomodulin (sTM). The average decrease in these markers was about 9%. In women treated with trimegestone the decreases were larger than in those treated with dydrogesterone; for sICAM-1 (-15% vs. -2%; P0.0001), sVCAM-1 (-15% vs. +3%; P = 0. 003) and sTM (-9% vs. -4%; P = 0.11). Plasma levels of endothelin-1 (ET-1) decreased (by 13%) only in women treated with E2 + P. In the E2 group, flow-mediated, endothelium-dependent vasodilatation increased by 6 percentage points after 12 weeks (P = 0.07 vs. baseline, P = 0.02 vs. E2 + P, and P = 0.17 vs. placebo).Short-term treatment with E2 or E2 + trimegestone reduces plasma levels of sICAM-1, sVCAM-1 and sTM. ET-1 decreased only in the E2 + P groups. Different types of progestagens may differentially affect sICAM-1, sVCAM-1 and sTM levels, which may be relevant for the choice of type HRT.

Currently, hormone replacement therapy is applied successfully to reduce post-menopausal bone resorption. However, the exact mechanism by which oestrogen exerts its effect has not yet been fully elucidated. In order to determine whether changes in the biologically active 1,25-dihydroxyvitamin D3 may be of importance in this process, the concentrations of both total and free 1,25-dihydroxyvitamin D3 in serum were assessed.In 36 post-menopausal women the effect of hormone replacement therapy, with a combination of 17 beta-oestradiol and norethisterone acetate, on the serum levels of total and free 1,25-dihydroxyvitamin D3 was studied after 0, 3, 6 and 12 cycles.The total concentration of 1,25-dihydroxyvitamin D3 in serum was assessed using a radioreceptor assay after diethylether extraction of the samples followed by paper chromatography. The free fraction of 1,25-dihydroxyvitamin D3 was measured using symmetric dialysis. The free 1,25 dihydroxyvitamin D3 concentration was calculated by multiplying the total concentration by the free fraction.During therapy, mean serum total 1,25-dihydroxyvitamin D3 concentrations (+/- SD) were 106.4 pmol/l (+/- 27.5), 155.0 pmol/l (+/- 49.5), 176.7 pmol/l (+/- 70.0) and 161.1 pmol/l (+/- 55.3) at 0, 3, 6 and 12 cycles, respectively. Serum free 1,25-dihydroxyvitamin D3 concentrations were 68 fmol/l (+/- 22), 107 fmol/l (+/- 35), 120 fmol/l (+/- 43) and 108 fmol/l (+/- 37), respectively. Baseline values of both total and free 1,25-dihydroxyvitamin D3 were significantly lower than those during therapy at all time (Por = 0.001).Both the serum total 1,25-dihydroxyvitamin D3 and the serum free 1,25-dihydroxyvitamin D3 concentrations are increased during combined 17 beta-oestradiol and norethisterone acetate therapy for a year. Assuming that the free concentration 1,25-dihydroxyvitamin D3 reflects the biologically active fraction, this rise may in part explain the preventive effect of hormone replacement therapy on osteoporosis.

Hyperhomocysteinemia is an independent cardiovascular risk factor, possibly through the induction of endothelial dysfunction. The postmenopausal state is associated with increased plasma homocysteine. We examined whether increased homocysteine is associated with impaired endothelial function.Sixty-three hysterectomized but otherwise healthy postmenopausal women (54.8 +/- 3.5 years) participated in this study. Fasting total plasma homocysteine (tHcy) was measured as free plus protein-bound homocysteine. Endothelial function was assessed by measuring plasma concentrations of the endothelium-derived proteins endothelin (ET), von Willebrand factor (vWF), and plasminogen activator inhibitor type 1 (PAI-1) as well as brachial artery flow-mediated, endothelium-dependent vasodilatation (FMD).Plasma tHcy was 9.6 +/- 2.5 micromol/L. After adjustment for possible confounders, a 1 micromol/L increase in tHcy was associated with an increase in ET of 0.08 ng/L (P = 0.045) and an increase in vWF of 4.2% (P = 0.05). No statistically significant association was present between tHcy and PAI-1 or FMD.Increased fasting homocysteine in postmenopausal women may impair some aspects of endothelial function. It is of clinical interest to study whether homocysteine lowering can improve endothelial function and thus cardiovascular morbidity and mortality in postmenopausal women.

Lipoprotein(a) [Lp(a)] is an independent risk factor for atherosclerosis. Serum Lp(a) concentrations increase after menopause, and postmenopausal estrogen replacement appears to decrease Lp(a) levels. In a randomized, double blind study, we examined the effects of 6-month treatment with daily 17 beta-estradiol (E2; 2 mg, orally) continuously combined with one of four dosages [2.5 mg (n = 41), 5 mg (n = 38), 10 mg (n = 38), and 15 mg (n = 20)] of dydrogesterone on fasting serum Lp(a) concentrations in 137 healthy postmenopausal women. At baseline, no significant differences were noted among the four treatment groups. During the study period of 6 months the median serum Lp(a) concentration decreased significantly from 128 mg/L (range, 5-1660) to 110 mg/L (range, 1-1530) in the total population, corresponding to a reduction of 13% (P0.001). The percent changes in serum Lp(a) correlated positively with the percent changes in serum E2 at 3 as well as 6 months of therapy (r = 0.38; P0.001 and r = 0.35; P0.001, respectively). A dose response of dydrogesterone on serum Lp(a) was not found. In addition, serum lipids and (apo)lipoproteins improved significantly in all four treatment groups. In conclusion, oral E2 continuously combined with dydrogesterone has beneficial effects on the lipid and lipoprotein profile and is effective in lowering Lp(a) concentrations in postmenopausal women.

This study was designed to compare the efficacy and safety of two sizes of Lyrelle, a new matrix design transdermal oestrogen patch, with Estraderm TTS 50, a reservoir system. Three hundred and ninety-four (394) hysterectomised postmenopausal women between 30 and 65 years of age participated in this open-label, randomised, multicentre clinical trial. The main efficacy criterion was the reduction in the mean number of hot flushes per day at six months. Secondary efficacy end points included other climacteric symptoms as well as various psychofunctional and genitourinary disorders. A significant decrease from baseline in the mean number of hot flushes/day was observed in all three groups from the end of cycle 1, reaching 90% at the end of cycle 7. there was no statistically significant difference between Lyrelle 50 and Estraderm at any time point for any parameter; however, between-group differences between Lyrelle 80 and Estraderm for various parameters were seen in the first three cycles in favour of Lyrelle 80. A similar impact on blood lipid levels was observed in all three groups, without significant between-group differences. We conclude that the new Lyrelle patch is a highly effective system for transdermal oestrogen replacement therapy that may enhance long-term patient compliance.

Osteoporosis is a common disorder in postmenopausal women, which is probably due to decreased ovarian function. Currently, hormone replacement therapy (HRT), involving administration of estrogen and progestogen, is successfully applied to reduce bone resorption. We studied the effect of HRT on 23 postmenopausal women. This consisted of a combination of 17 beta-estradiol and dydrogesterone, on the serum level of 1,25-dihydroxyvitamin D (1,25(OH)2D) after 0, 6, 12, and 24 months. We found mean serum concentrations (+/- SD) of 1,25(OH)2D of 130.5 pmol/liter (46.1), 152.7 pmol/liter (45.1), 170.8 pmol/liter (64.0), and 155.2 pmol/liter (59.7), respectively. The baseline values in these women were found to be significantly lower than those during therapy (Por = 0.005). No statistically significant differences were observed when comparing the estrogen-only phase with the combined estrogen-progestogen phase. It is concluded that HRT results in an increase in the serum 1,25(OH)2D concentration which lasts for at least 2 years. This increase may partly explain the preventive effect of HRT on osteoporosis. Furthermore, these results suggest that dydrogesterone does not influence the estrogen-induced changes in serum 1,25(OH)2D concentration.