Bleeding pattern and climacteric symptoms during different sequential combined HRT regimens in current use

Four sequential combined oestrogen and progestogen regimens were compared in terms of bleeding pattern and relief of climacteric symptoms. Treatment was with either 2 mg 17β-oestradiol with I mg norethisterone acetate [E₂ + NEta]; 2 mg oestradiol valerate with 75 μg levonorgestrel [E₂V + Lng]; 2 mg oestradiol valerate with 10 mg medroxyprogesterone acetate [E₂V + Mpa]; or 1.5 mg 17β-oestradiol with 150 βg desogestrel [E₂ + DG]. A placebo-controlled study lasting 12–24 months was completed by 143 healthy early postmenopausal women. Bleeding lengths were not substantially different; in all regimens the majority of women were bleeding for 3–6 days. Bleeding onset showed differences when related to the 11th day of progestogen addition; in the regimen with E₂V + LNG, 21% of the women were bleeding before the 11th day of progestogen addition 26% on, and 53% after that day. In the regimen with E₂V + MPA, 56% of the women were bleeding before the 11th day, 28% on, and 17% after that day, whereas in the regimen with E₂ + DG, 15% of the women were bleeding before the 11th day, 5% on, and 80% after that day. All regimens reduced climacteric symptoms to the same extent. Breast tenderness occurred in all the regimens, except in the E₂ + DG. Conclusively, the differences between the responses to treatment were not conspicuous. However, our data indicate that one regimen (E₂ + DG) resulted in optimal bleeding control, optimal effect on climacteric symptoms, and no production of breast tenderness.     

The effects of continuous combined transdermal oestrogen-progestogen treatment on bleeding patterns and the endometrium in postmenopausal women

Fifty postmenopausal women requiring hormone replacement therapy for the treatment of climacteric symptoms were recruited in six centers. All patients received a new combined norethisterone acetate (NETA)/oestradiol (E₂)-TTS, (Estragest TTS, Ciba-Geigy Ltd), delivering 0.25 mg NETA and 50 μg E₂ per day, continuously for 12 calendar months. Bleeding occurred in 38 (76%) of the 50 patients at any time during the 1 year treatment. The percentage of patients without bleeding increased gradually each month, from 24% in the second month to a relatively stable level of 80% in month 7 and thereafter. Twenty-seven patients (54%) did not complete the whole trial period; 15 of which discontinued the treatment within the first few months due to irregular bleeding. In patients who remained in the trial, a clear decrease in the frequency and intensity of the bleeding was observed with time. Bleeding was mostly light or consisted of spotting only. None of the post-trial biopsies showed proliferation or hyperplasia of the endometrium. The treatment resulted in a substantial decrease of climacteric symptoms (Kupperman index) within 4 months and was well tolerated. It was concluded that the continuous NETA/E₂-TTS treatment is an effective and safe alternative for the treatment of climacteric symptoms in selected patients.     

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.     

Bleeding patterns in peri and postmenopausal women taking a continuous combined regimen of estradiol with norethisterone acetate or a conventional sequential regimen of conjugated equine estrogens with medrogestone

Objectives: The aim of this study was to compare the incidence of women presenting irregular bleeding episodes following 9 months of treatment with a low dose continuous combined hormone replacement therapy consisting of estradiol (E₂) and norethisterone acetate (NETA) versus a sequential hormone replacement therapy consisting of conjugated equine estrogens (CEE) and medrogestone (MG). Secondary aims were to establish the relationship between menopausal age and the occurrence of irregular bleeding for both therapies and to assess the efficacy of both therapies in alleviating menopausal symptoms. Methods: This was a stratified and randomised, open label study conducted with late peri and postmenopausal women at 35 sites in Austria and Germany. A total of 446 women were randomly allocated into two cohorts based on time since last bleeding and then stratified to either a low dose continuous combined therapy consisting of 1 mg E₂ and 0.5 mg NETA for 28 days or a sequential therapy consisting of 0.625 mg CEE for 28 days and 5 mg MG for the final 14 days. Bleeding and menopausal complaints were continuously assessed. Treatments were administered for 9 lunar months. Results: The incidence rate of women presenting irregular bleeding episodes including spotting during cycle 9 was 12.2% with 1mgE₂/0.5mgNETA and 25.8% with 0.625mgCEE/5mgMG (P=0.0014). In the group of postmenopausal women (time since last bleeding 12 months) the incidence of irregular bleeding during cycle 9 was 11.0% for 1mgE₂/0.5mgNETA and 25.0% for 0.625mgCEE/5mgMG). In the group of late perimenopausal women (time since last bleeding 6–11 months) the incidence of irregular bleeding was similar for both treatments at cycle 3, but markedly less in patients with 1mgE₂/0.5mgNETA at cycle 6 and 9, being significantly different compared to patients with 0.625mgCEE/5mgMG at cycle 6 (P<0.05). The cumulative rate of amenorrhea (no bleeding or spotting) achieved with 1mgE₂/0.5mgNETA was 89% for the postmenopausal women and 83.7% for the late perimenopausal women. Both treatments relieved menopausal complaints equally effective. Conclusions: Regarding the occurrence of irregular bleeding, the low dose continuous combined therapy was superior to the sequential therapy (0.625mgCEE/5mgMG). The low dose continuous combined E₂/NETA regimen is also suitable for late perimenopausal women since more than 80% of the women had no bleeding or spotting after 9 months of treatment.     

17β-estradiol and norethisterone acetate in low doses as continuous combined hormone replacement therapy

Objectives: To evaluate low doses of 17β-estradiol (E2) and norethisterone acetate (NETA) as continuous combined hormone replacement therapy (HRT) in their effects on vasomotor symptoms, bleeding episodes, endometrial histology and mastalgia. Method: Sixty postmenopausal women were randomly allocated to three treatment groups and were given 1 mg E2 and 0.25 mg NETA (A), 1 mg E2 and 0.5 mg NETA (B) and 2 mg E2 and 1.0 mg NETA (C) in daily doses. The treatment period was 1 year. Results: A similar statistically significant reduction of climateric symptoms (P < 0,05) was found in all groups. Bleedings, mainly as spottings, occurred most commonly during the first treatment months. Fewer bleeding episodes and a higher percentage of amenorrhea was noted in group B compared to the other groups but did not reach statistical significance. All endometrial biopsies showed atrophy. Women in group A and B had less severe mastalgia (P < 0,05) compared to group C, given higher doses of steroids. Conclusion: Postmenopausal women taking 1 mg of E2 plus 0.5 mg NETA as continuous combined HRT reported a marked reduction of climacteric complaints and good bleeding control. No endometrial proliferation was detected after 1 year of treatment. This type of therapy may be beneficial especially for elderly women, in whom bleeding may be annoying.     

Pharmacokinetics and biotransformation of orally administered oestrone sulphate and oestradiol valerate in post-menopausal women

The pharmacokinetic properties and biotransformation of two orally active oestrogens, piperazine oestrone sulphate (PE₁S, 2.5 mg/day) and oestradiol valerate (E₂V, 2.0 mg/day), given alone or in combination with levonorgestrel (LNG, 250 μg/day) were compared in 8 post-menopausal women, using a randomized cross-over design.

The end points measured in peripheral plasma included oestrone (E₁), oestradiol (E₂), oestriol (E₃), oestrone sulphate (E₁S), oestradiol sulphate (E₂S) and oestriol sulphate (E₃S). In addition, LNG and sex-hormone-binding globulin SHBG concentrations were also assessed.

The plasma levels of E₃ were invariably below the detection limit (220 pmol/1). The levels of all the other oestrogens analyzed were consistently higher and the area under the curve significantly greater (except in the case of E₃S following PE₁S administration than those recorded after E₂V ingestion.

The terminal half-lives of the circulating oestrogens measured after PE₁S administration did not differ from those found after E₂V administration.

After 21 days of PE₁S administration (in combination with LNG for the the last 10 days), the maximum levels of all the oestrogens (except those of E₂) were significantly higher than those seen after the first dose. No such difference was observed after E₂V administration.

There was no difference between the effects of the two treatment regimens with regard to the E₁/ E₂ ratios, but the E₁/E₁S ratios were significantly lower after PE₁S treatment than after E₂V administration.

It is concluded that, compared with an equivalent dose of PE₁S, daily repeated oral administration of E₂V yields consistently lower peripheral plasma levels of E₂ and its principal metabolites. However, in contrast to PE₁S therapy, prolonged administration of E₂V does not result in an accumulation of the circulating oestrogens measured.     

Comparative endocrinological and clinical effects of percutaneous estradiol and oral conjugated estrogens as replacement therapy in menopausal women

Sixty-three healthy post-menopausal women participated in the study aimed at determining the efficiency of percutaneous administration of estradiol (E₂) giving physiological plasma levels of the estrogen to provide an efficient relief of climacteric and urogenital symptoms. Among these women, 31 had previous hysterectomy and were randomly allocated to one of the two estrogen replacement therapies while, similarly, the 32 women having an uterus were randomly divided between two groups who received in addition to estrogens, micronized oral progesterone. As estrogen, women received either E₂ by percutaneous administration (Oestrogel) or oral conjugated estrogens (Premarin). With Oestrogel, serum E₂ and estrone levels were within those seen during premenopause and showed a ratio close to 1.0. Climacteric symptoms were reduced or eliminated similarly in all groups. No change was noticed on the concentration of serum angiotensinogen with Oestrogel therapy while a 2.5-fold increase was found in women receiving Premarin. As indicated by the 24-week endometrial biopsy, the progestational response induced by oral progesterone at the dose used was sufficient in twenty out of thirty-two women to cause endometrial atrophy, thus suggesting the need for higher amounts of micronized progesterone in a proportion of women. The present data also indicate that Oestrogel provides efficient relief of climacteric and urogenital symptoms without exerting any detectable effect on hepatic function while maintaining the ratio of serum E₂/E₁ at the physiological value of 1.0.     

Postmenopausal uterine bleeding profiles with two forms of continuous combined hormone replacement therapy.

OBJECTIVE: This study was designed to compare the bleeding profiles of conjugated equine estrogens 0.625 mg in combination with 2.5 mg medroxyprogesterone acetate (Prempro; CEE/MPA group), the most widely prescribed continuous combined hormone replacement therapy (CCHRT) in the United States, with 17beta-estradiol 1 mg combined with 0.5 mg norethindrone acetate (Activella; E(2)/NETA group), a newly available CCHRT preparation, over a 6-month period. DESIGN: This study was a prospective, randomized, multicenter, double-blind, controlled trial. A total of 438 healthy postmenopausal women were randomized and received treatment (Activella n = 217, Prempro n = 221). Each woman recorded bleeding diaries daily. Total cholesterol, triglycerides, and endometrial biopsies were obtained at screening and end-of-trial visits. RESULTS: The more favorable bleeding profile was found in the E(2)/NETA (Activella) group. The differences in bleeding patterns were most marked in the first 3 months of treatment in women who were 1-2 years from last menses, with no bleeding in 71.4% vs. 40.0%; ( p = 0.005) and with no bleeding and no spotting in 54.8% vs. 17.1%; (p = 0.001). Triglycerides fell by 8.5% in the E(2)/NETA group and increased by 11.7% in the CEE/MPA group (p < 0.001). Total cholesterol declined by 9.1% and 6.9%, respectively. CONCLUSION: The most important factor in the continuation of HRT is uterine bleeding. E(2)/NETA has significantly less bleeding than the most commonly prescribed CCHRT CEE/MPA, therefore; E(2)/NETA should be associated with improved continuation rates. The patient taking E(2)/NETA will receive effective treatment for her menopausal symptoms with less bleeding.     

The effect of oral hormone replacement therapy on lipoprotein profile, resistance of LDL to oxidation and LDL particle size

Objectives: To disclose if oral estradiol (E₂), alone or in combination with natural progesterone (P) or medroxyprogesterone acetate (MPA), may modify the oxidizability of low density lipoprotein (LDL), and if the effect is achieved at physiological dosages. LDL oxidizability was assessed by the resistance to oxidation by copper and by the particle size profile, since small particles have increased oxidation susceptibility. Methods: Thirty-three women received two consecutive, two-month length doses of 1 and 2 mg/day of oral E₂. They were then randomly assigned to a fourteen-day treatment of 2 mg/day E₂ plus either 300 mg/day P or 5 mg/day MPA. A parallel group of experiments was performed on a pool of baseline plasma, where hormones were added at the desired concentration. Lipoprotein levels, resistance of LDL to oxidation, and LDL particle diameter, were measured at baseline and after each treatment. Results: Estradiol reduced LDL levels and increased high density lipoprotein (HDL) and triglycerides. P abolished these changes, whereas MPA only reversed the increase of HDL. Estradiol protected LDL from oxidation in a dose-dependent manner, although only at pharmacological concentrations (1 μM or higher). Both P and MPA were inert at either physiological or pharmacological concentrations. The size of the LDL particles remained unaffected except under MPA, in which it was reduced. Conclusions: Estradiol has a protective effect against LDL oxidation, although only at pharmacological dosages. P and MPA did not limit the E₂ action. The size of the LDL particles remained unaltered after each E₂ dose, but MPA, and not P, was associated with a diminution.     

Hormone levels in healthy post-menopausal women and in women with post-menopausal bleeding with or without endometrial carcinoma

FSH, oestrone (E₁), 17β-oestradiol (E₂) and androstenedione (A) were determined in 250 healthy pre- and post-menopausal women, with ages ranging from 40 to 78 yr. These hormone levels were not found to have changed significantly in women of this stable, post-menopausal phase after the age of 54. The results found in this group of women (n = 107), who now range between the ages of 55 and 78, were compared with results from two groups of women who were found to have gynaecological disorders. The first group consisted of 45 women with post-menopausal bleeding without endometrial carcinoma. The second group consisted of 38 women with post-menopausal bleeding and endometrial carcinoma.

FSH was determined by double-antibody radioimmunoassay. E_l, E₂ and A were fractionated chromatographically after extraction with ether and determined radioimmunologically. The data were analysed using the Kruskal—Wallis test and the Wilcoxon test.

When comparing the measurement of hormone levels in the healthy group of women with that of women with post-menopausal bleeding without endometrial carcinoma, no differences were found. However, in the group of women with post-menopausal bleeding and endometrial carcinoma, lower levels of FSH and E₂ and increases in the E₁/E₂ ratio were found; both changes were statistically significant. The slight increase in E₁ and A found in these women was not significant. Any changes which occur in the hormone levels of women with endometrial carcinoma may indicate a correlation between hormones and the onset of endometrial carcinoma.     

Apoptosis, proliferation, and sex steroid receptors in postmenopausal endometrium before and during HRT

OBJECTIVES: Endometrial homeostasis, indicated as the balance between apoptosis and proliferation, was studied with regard to endometrial safety and bleeding disturbances. MATERIALS AND METHODS: The quantitatively sufficient endometrial biopsies of 92 postmenopausal women enrolled in the study were investigated. The participants were divided into two groups, each receiving a continuous combined HRT regimen with either conjugated estrogen (CE) 0.625 mg + 5 mg medroxyprogesterone acetate (MPA) (=CE/MPA) or 17-beta-estradiol (E2) 2 mg + 1 mg norethisterone acetate (NETA) (=E2/NETA). These were evaluated according to apoptotic index (Ai) and proliferation marker Ki-67 index. Estrogen receptor alpha (ER) and progesterone receptor (PR) expression were also monitored, as well as endometrial thickness. Quantitative in situ techniques were used. RESULTS: Ai and Ki-67 index were unchanged in epithelial glands of endometrium from baseline to second biopsy obtained after 1 year of combined continuous HRT. In stromal tissue, Ki-67 index was increased, while Ai was on the same level. PR expression in both epithelium and stroma was unchanged. Endometrial thickness was unaffected during therapy, and the histopathological evaluation showed no development of hyperplasia or carcinoma. CONCLUSIONS: The unaffected homeostasis in endometrial epithelium contributes to endometrial safety and is in accordance with the histopathological findings of no hyperplasia. The homeostasis of stroma was transformed to be more proliferative. Increased stromal proliferation may be of importance for stromal support of the veins and for decreasing breakthrough bleeding during HRT. The increased stromal proliferation, as well as the decreased ER expression both in epithelium and stroma, could be an effect of progesterone.     

Plasma androstenedione and oestrone levels in the climacteric syndrome

Plasma androstenedione (A) and oestrone (E₁) levels were measured by radioimmunoassay in a group of 78 healthy women who had undergone a natural menopause. Of this total, 23 were symptomless (Group 1), 39 presented with a moderate climacteric syndrome (Group 2) and 16 had a severe climacteric syndrome (Group 3). The average body weight was found to be significantly higher in Groups 2 (P < 0.01) and 3 (P < 0.05), than in Group 1, but the age distribution and number of years since the menopause were similar in all three groups. Nevertheless, significantly lower levels of A (0.75± 0.06 ng/ml, P < 0.01, in Group 2; 0.24 ± 0.05 ng/ml, P < 0.001, in Group 3) and E₁ (20.80 ± 2.18 pg/ml, P < 0.05, in Group 2; 12.22 ± 1.65 pg/ml, P < 0.001, in Group 3) were observed in the women with climacteric symptoms than in those with no symptoms (A = 1.08 ± 0.08 ng/ml, E₁ = 27.73 ± 2.22 pg/ml in Group 1).

Since, after the menopause, the concentrations of A and E₁ in the plasma represent the most important source of oestrogens, these results suggest that climacteric symptoms are related to oestrogen deficiency which is secondary to low A production.     

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.     

Prospective,randomised study with three HRT regimens in postmenopausal women with an intact uterus

Objective: To compare compliance, symptom control, bleeding patterns, lipid and biochemical changes in postmenopausal women treated with three regimens of HRT. Methods: In a prospective, randomised, group comparative study, with 165 patients, the effects on the aforementioned parameters, as well as treatment compliance and side effects were studied with oral tibolone 2.5 mg per day, with cyclic combined regimen of transdermal oestrogen and progestogen (transdermal patch of 17β-oestradiol 50 μg/day during 14 days and transdermal patch of 17β-oestradiol 50 μg/day plus 0.25 mg/day NETA during the following 14 days), and with intermittent progesterone regimen (transdermal 17β-oestradiol 50 μg/day and oral micronised natural progesterone 200 mg twice a week). Statistical analysis was carried out using the Fisher-test, analysis of the variance (ANOVA) and the Bouferoni test. Results: Ten women dropped out of the tibolone group, 11 dropped out of the intermittent dosing group and 21 dropped out of the cyclid combined group. Irregular bleeding occurred at more rates in the cyclid combined group. Similar reductions in climacteric symptoms were found in the three groups. No differences were observed with respect to biochemical analysis. Conclusions: Efficacy and safety of the three treatment regimens being comparable, but the patients in our study preferred those that did not produce bleeding episodes.     

A comparative study of two hormone replacement therapy regimens on safety and efficacy variables

Objective: To assess the effect of tibolone on endometrial safety, plasma estradiol concentrations, lipid metabolism and climacteric symptoms in comparison to sequential conjugated equine estrogens and medroxyprogesterone acetate in postmenopausal women. Methods: In a randomised, open-label, 6-cycle, group-comparative study, the effects on the aforementioned parameters were studied with tibolone 2.5 mg/day (N = 13) continuously, and with conjugated equine estrogens 0.625 mg/day continuously, combined with medroxyprogesterone acetate 5 mg/day (N = 11) (CEE/MPA) sequentially, during 12 days of each 28-day cycle. Within-group statistical analysis was performed with Student's t-test for paired samples, whereas between-group statistics were performed using the Student's t-test for independent groups. Results: Cytological evaluation revealed no endometrial stimulation in either group. In the tibolone group, there were no effects on estradiol levels, whereas in the CEE/MPA group, an increase in total and non-SHBG-bound estradiol plasma levels was reported. In the tibolone group, there were significant decreases in plasma total cholesterol, triglycerides, HDL-cholesterol and VLDL-cholesterol, whereas no significant changes in LDL-cholesterol and IDL-cholesterol were reported. In the CEE/MPA group there were significant decreases in plasma total cholesterol, HDL-cholesterol and LDL-cholesterol, whereas there were no significant changes in triglycerides, IDL-cholesterol and VLDL-cholesterol. Climacteric symptoms, particularly vasomotor episodes, decreased similarly in both groups. Conclusions: Both tibolone and CEE/MPA were safe with respect to effects on the endometrium and both treatments induced changes in the plasma profiles of certain lipid and lipoprotein parameters. However, the overall clinical implications of these changes are unknown. Finally, both regimens were equally effective in the treatment of climacteric symptoms     

Benefits and risks of different hormonal replacement therapies in post-menopausal women

A total of 113 women who presented with climacteric symptoms participated in the study. They were randomly allocated to seven groups of 10–27 subjects, who received for 6 mth the following therapies, respectively: (1) conjugated oestrogens (CE) 0.625 mg/day for 21 days + norethisterone (NET) 5 mg/day from day 12 to day 21; (2) CE + cyproterone acetate (CPA) 12.5 mg/day from day 1 to day 10; (3) oestradiol valerate (EV) 2 mg/day for 21 days + NET; (4) EV + CPA; (5) oestriol (E₃) 2–4 mg/day; (6) tibolone (ORG OD14) 2.5 mg/day; and (7) placebo, one tablet/day.

Hot flushes decreased significantly over the treatment period in all seven groups. However, E₃ was less effective at the dose used than CE, EV or ORG OD 14. At the end of the 6 month treatment period histological examination revealed no changes in endometrial morphology in any of the patients treated. Indeed, the addition of a progestogen even induced regression of endometrial hyperplasia in 8 cases.

No significant variation in the plasma levels of tryglycerides, total cholesterol, high-density lipoprotein (HDL) or low-density lipoprotein (LDL) was observed after the second and sixth months of treatment with E₃ or ORG OD 14. After 6 months, treatment with CE/EV + CPA produced a significant increase in HDL, while treatment with CE/EV + NET brought about a reduction in total cholesterol and HDL and an increase in LDL.     

A comparison of the effects of ethinyl estradiol and estradiol valerate on serum and lipoprotein lipids

Serum lipids and lipoproteins were assessed after treatment with 2 mg of oestradiol valerate (E₂V) and 10 μg of ethinyl oestreadiol (EE) in a group of 24 oophorectomised women in a study with an open cross-over design.

E₂V in this oral dose was quite inert in its effect on lipoprotein lipids. Ten micrograms of EE is a dose which in most women is sufficient to alleviate post-menopausal vasomotor symptoms. However, this low dose of EE increased serum triglycerides as a result of increased levels in the ultracentrifugally isolated lipoprotein fractions. Increased levels of serum and lipoprotein triglycerides are considered cardiovascular risk factors in women.     

Continuous-combined treatment of the menopause with combinations of oestradiol valerate and dienogest - a dose-ranging study

Objectives: To determine the progestational efficacy of continuous treatment with various doses of dienogest, combined with oestradiol valerate, on the basis of endometrial histology, effect on climacteric symptoms and bleeding profile in postmenopausal women. Methods: Patients were randomised to one of five fixed-combination treatments, oestradiol valerate 2.0 mg plus dienogest 0.5, 1.0, 2.0, 3.0 or 4.0 mg. Efficacy was assessed by endometrial biopsy, menstrual charts and change in climacteric symptoms. Results: The endometrium was classified as atrophic in 20.0, 31.3, 25.0, 55.6 and 57.1% of patients in the 0.5, 1.0, 2.0, 3.0 and 4.0 mg dienogest groups, respectively. The frequency of uterine bleeding was dose-dependent. The most favourable bleeding profile was seen in the 3.0 mg dienogest group, whereas the lower doses of dienogest had advantages with respect to the efficacy of the combined preparation. Conclusions: Dienogest 2.0 and 3.0 mg are the optimal doses for combination with 2.0 mg oestradiol valerate for continuous-combined hormone replacement therapy.     

Can climacteric women self-adjust therapeutic estrogen doses using symptoms as markers ?

Objectives: To investigate if disappearance of climacteric symptoms during hormone replacement therapy (HRT) also means good therapeutic level of serum estradiol. The study group comprised of 32 postmenopausal women who had frequent climacteric symptoms. Methods: The women increased the daily treatment doses of percutaneous estradiol every 2 weeks until they felt comfortable with it. Each woman continued at that treatment dose for up to 3 months. Blood samples for estradiol assay were drawn at baseline, every time before the estradiol dosage was increased and at the end of the study. Climacteric symptoms were scored according to the Kupperman menopausal index. Results: Despite the relief of climacteric symptoms, serum estradiol concentration was at a menopausal level (<50 pg/ml) in 22% of the women. In all, 45% of the subjects showed serum estradiol remaining under 60 pg/ml, 29% of the women showed levels of 60–100 pg/ml and 26% showed serum estradiol concentration more than 100 pg/ml. Conclusions: The disappearence of climacteric symptoms during HRT does not quarantee that estrogen levels are sufficiently high for obtaining long term benefits of HRT.     

Antagonism of oestrogen-induced prolactin release by medroxyprogesterone acetate

Previous studies conducted at our clinic suggested that the administration of hormone replacement therapy (HRT) in postmenopausal women could result in the inhibition of oestrogen-induced prolactin (PRL) release. The aim of this study was to determine how the pituitary function is affected by the sequential addition of medroxyprogesterone acetate (MPA) to oestrogen replacement therapy. Twenty-one postmenopausal women receiving no other medication were treated with a standard dose (0.625 mg/day) of conjugated equine oestrogens (CEE) for a period of 24 days, plus 5 mg/day MPA added sequentially during the last 12 days of the oestrogen therapy. Blood samples were collected before treatment, during oestrogen and oestrogen-progestogen administration and after cessation of treatment. Folliclestimulating hormone (FSH), luteinizing hormone (LH), 17β-oestradiol (E₂) and PRL levels were studied. During treatment gonadotrophin concentrations decreased significantly, while after cessation of HRT the levels of FSH and LH increased. These gonadotrophin fluctuations indicated a sharp rise in E₂ levels during therapy and a significant decrease during the treatment-free period. PRL levels were found to be higher during CEE therapy, but they fell when patients received CEE in combination with MPA. These observations suggest that the role of progestogens in a variety of experimental and clinically relevant situations needs to be investigated not only as regards their direct action but also their modulation of the effect of oestrogen.