Effects of oestradiol administration via different routes on the lipid profile in women with bilateral oophorectomy

To determine the influence of various oestrogenenic administrations on lipid response, 63 women with total abdominal hysterectomy and bilateral anexectomy were studied before and 6 and 12 months after receiving 17β-oestradiol by different means. The effect on the levels of lipids and lipoproteins of the 2 mg/24 h administration of oestradiol valerate was compared with 1.5 mg/day of percutaneous 17β-oestradiol and 0.05 mg/day of transdermic oestradiol. The treatments were given continuously over a year. The oestradiol valerate produced a statistically significant increase (P < 0.05) of the HDL-C levels both after 6 and 12 months (10.6% vs. 11.6%). A significant increase was also observed (P < 0.05) in the Apo Al levels during the treatment (18 and 25%). On the other hand, unfavorable side effects with oestradiol were not produced, either percutaneous or transdermic, on lipid plasmatic or lipoprotein levels. These data show the benefit of oral oestrogenic therapy and the maintenance of the lipid profile in percutaneous and transdermic therapies in oophorectomized women.     

The effect of percutaneous oestrogen replacement therapy on Lp(a) and other lipoproteins

Objectives: To determine the effect of percutaneous oestrogen replacement therapy on lipoprotein (a) and other plasma lipoproteins. Methods: Open longitudinal prospective study conducted at the hormone replacement clinic of the Prince of Wales Hospital, New Territories, Hong Kong. Thirty women who had undergone a total abdominal hysterectomy and bilateral salpingo-oophorectomy for benign gynaecological conditions were treated with 1.5 mg of percutaneous 17β-oestradiol gel applied daily for a period of 12 consecutive months. Measurements of plasma lipoproteins were made before the commencement of treatment and repeated at 6- and 12-month intervals. Results: There was a significant reduction in the concentrations of Lp(a) during the first 6 months of treatment, with median values falling from 7.87 mg dL⁻¹ to 6.16 mg dL⁻¹ (P = 0.004, 0–6 months). During the second 6 months, the median concentration increased to 9.38 mg dL⁻¹, (P = 0.072, 66-12 months), which did not significantly differ from the baseline level (P = 0.545, 0–12 months). Significant reductions in the concentrations of apoprotein A-I (apo A-I), apoprotein B (apo B), high density lipoprotein cholesterol (HDL-C), and HDL₃-C were also present after 6 months (P = 0.043, 0.049, 0.028, 0.013, respectively), but there were no differences between the baseline values of these lipoproteins and those at the completion of the study (P = 0.948, 0.244, 0.839, 0.117 respectively). Drug compliance was maintained throughout the study, with similar mean oestradiol concentrations at 6 and 12 months. Conclusions: The percutaneous administration of 17β-oestradiol has variable short term effects on plasma lipoproteins which are not maintained over a longer duration of treatment. By avoiding the ‘first pass’ effect on the liver, this method of delivery does not appear to produce the sustained changes in lipoproteins seen with oral treatment.     

Pharmacokinetic and pharmacological features of oestradiol valerate

Natural oestrogenic hormones are the appropriate substances for the therapy of climacteric complaints. After oral or parenteral administration, oestradiol valerate, the synthesis compound contained in various commercially available preparations, is completely converted into the natural substances 17β-oestradiol and valeric acid. The 17β-oestradiol produced on cleavage of the ester behaves in the organism like the endogenous steroid hormone. Oestradiol valerate and 17β-oestradiol are virtually dose-equivalent. No differences in the spectrum of action of the oestrogen and its ester have been found either in animal experiments or man. The pharmacokinetic behaviour and the biotransformation of the 17β-oestradiol originating from oestradiol valerate are no different from those of natural 17β-oestradiol. Differences of practical significance exist in respect of the quantitative effect of oestradiol valerate following oral and intramuscular administration, whereas 4 mg oestradiol valerate administered intramuscularly is therapeutically sufficient for a period of 2–4 wk (depot effect). As much as 2 mg daily over 3 wk must be administered via the oral route to achieve the same effect. This difference is due to the greatly diverging pharmacokinetic behaviour of oestradiol valerate depending on which of the two modes of administration is employed.     

Haemodynamic and hormonal effects of short-term oestradiol treatment in postmenopausal women

Haemodynamic changes during a 3-wk treatment with oestradiol valerianate (2 mg/day orally) were studied in 12 postmenopausal women by isotope ¹¹³In^m radiocardiography.

Systolic blood pressure measured in the supine position decreased during oestradiol treatment by 3% (P < 0.05) and the diastolic blood pressure decreased by 4% (P < 0.01). The heart rate decreased by 15% (P < 0.001).

Blood volume increased during oestrogen treatment by 5% (P < 0.05) whereas cardiac output decreased by 9% (P < 0.05). Stroke volume increased by 13% (P < 0.001) due to concomitant decrease in heart rate.

Changes in plasma oestrone and oestradiol concentrations during oestradiol valerianate substitution showed a positive correlation with the changes of blood volume.     

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.     

Effects of percutaneous oestradiol versus oral oestrogens on bone density

In order to compare the effects on bone density of 1.5 mg/day percutaneous 17β-estradiol (E₂) and of 0.625 mg/day oral conjugated oestrogens (CEE), 68 women who had undergone hysterectomy were studied. The subjects were randomly allocated to one of three study groups. A total of 15 women dropped out from these groups during the study. The percutaneous group (n = 20) received treatment for 36 months and the oral group (n = 17) for 24 months, while the untreated group (n = 16) served as controls over a period of 24 months. Bone mineral density (BMD) was measured by dual gammagraphic densitometry (Novo 22A densitometer) in the lumbar spine (L2-L4). The percentage gain in the percutaneous group was 1.7% ± 3.9% after 12 months, 5.6% ± 2.9% (P < 0.001) after 24 months and 4.7% ± 3.2% (P < 0.001) after 36 months. In the oral group the gain was 3.5% ± 13.0% after 12 months and 4.3% ± 9.2% (P < 0.001) after 24 months. In the untreated group the bone density loss was 6.6% ± 3.5% (P < 0.001) after 12 months and 9.1% ± 3.4% (P < 0.001) after 24 months. On the basis of our results we concluded that both 1.5 mg/day percutaneous E₂ and 0.625 mg/day oral CEE not only prevented bone loss but also increased BMD, as was confirmed by our findings after 36 and 24 months of treatment, respectively.     

The vaginal absorption of oestrogens in post-menopausal women

Serum E₁, E₂ and E₃ concentrations and E₂/E₁ ratio were measured after vaginal application of conjugated oestrogens, micronized 17β-oestradiol and oestriol. 2.4 mg of conjugated oestrogens caused a prompt elevation in the serum E₁ concentration; the E₂ level changed only slightly. After vaginal application of 2 mg micronized 17β-oestradiol the main serum oestrogen is E₂ and the conversion of E₂ to E₁, as in oral administration, does not occur. A significant elevation in the serum E₃ concentration was noted 2 h after the vaginal application of 0.5 mg oestriol. The E₂/E₁ ratio changed little after the application of conjugated oestrogens but increased considerably after the vaginal administration of 2 mg micronized 17β-oestradiol.     

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 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.     

Comparison of a triphasic oestradiol/norethisterone acetate preparation with and without an oestriol component in the treatment of climacteric complaints

This study was undertaken to evaluate the effects of oestriol in combination with oestradiol in the treatment of women with climacteric complaints. Forty-three post-menopausal women were randomly allocated to two groups on a double-blind basis. Over a 28-day cycle 23 of the women were treated sequentially for 12 days with 1 tablet containing 17β-oestradiol 2 mg plus oestriol 1 mg, then for 10 days with 1 tablet containing the same oestrogens plus norethisterone acetate 1 mg, thereafter for 6 days with 1 tablet containing 17β-oestradiol 1 mg plus oestriol 0.5 mg. The other 20 women received the same treatment but without the oestriol. No clinical, laboratory or histological differences were seen between the two groups. Both treatments were found to be equally effective in alleviating climacteric symptoms, with few side effects. It may be stated in conclusion that, on the basis of routine clinical and laboratory parameters no differences were found between the two preparations.     

Comparative metabolic study of percutaneous versus oral micronized 17β-oestradiol in replacement therapy

The aim of this study was to compare the metabolic effects of two presentations of 17β-oestradiol (E₂) which are of recognized effectiveness in the prevention of post-menopausal bone loss, one being administered via the oral and the other via the percutaneous route. During this prospective, randomized study, 32 patients were treated for 2 mth with either 2 mg/day of oral micronized E₂ (n = 16) or 3–5 mg/day of percutaneous E₂ (n = 16). Both regimens proved efficacious, since significant increases in oestrone (E₁) and E₂ concentrations ranging up to mid-follicular values were observed.

In the percutaneous-treatment group we noted a significant decrease in triglycerides (TG), without any significant changes in high-density lipoprotein cholesterol (HDL-C) or low-density lipoprotein cholesterol (LDL-C). In the oral-treatment group, we saw no significant increase in HDL-C, although significant increases were observed in body weight, TG, plasma renin substrate (PRS) and sexhormone-binding globulin (SHBG) as well as significant decreases in antithrombin III (AT III) activity and antigen. All of these metabolic variations led us to the conclusion that oral E₂ at the dose established as effective in preventing post-menopausal osteoporosis may, even when micronized, alter certain metabolic and haemostatic parameters in a population characterized by increases in cardiovascular risk factors and morbidity. Oral oestrogen replacement therapy should therefore continue to be used only in carefully selected patients and be strictly followed up by systematic checks on a series of metabolic criteria.     

Acute administration of 17beta-estradiol improves endothelium-dependent vasodilation in postmenopausal women

Objectives: Estrogen’s effect on endothelial function in postmenopausal women with mild hypertension but no other cardiovascular risk factors remains unclear. This study investigated the effect of an acutely administered therapeutic/low dose of 17β-estradiol on vasodilation in this patient population. Methods: Forearm blood flow (FBF) was measured in seven white, hypertensive (blood pressure 144 ± 8/93 ± 5 mmHg), postmenopausal (mean age: 54.4 ± 5 years) women at baseline and during the intra-brachial infusion of increasing doses of acetylcholine (ACh; 0.75, 5, and 15 μg/100 mL tissue/min) and sodium nitroprusside (NP; 1, 2, and 4 μg/100 mL tissue/min). These measurements were obtained both before and after the sublingual administration of 17β-estradiol. Eight normotensive women (blood pressure 115 ± 8/76 ± 5 mmHg) with otherwise similar characteristics served as controls (mean age: 55.8 ± 5 years). Exclusion criteria included medications or any condition that could alter endothelial function. Results: Before estradiol administration, FBF values at baseline and after all doses of ACh and NP were similar between groups. Acutely administered 17β-estradiol significantly improved the FBF response to ACh in both the normotensive (maximal response: 17.6 ± 5 versus 22.5 ± 7 mL/min/100 mL) and hypertensive (11 ± 4 versus 16 ± 6; 12 ± 4 versus 17 ± 5 and 14 ± 3 versus 20 ± 7 mL/min/100 mL) groups. It also altered the NP dose–response curve in the both groups. Conclusion: 17β-estradiol improved vasodilatory responses in mildly hypertensive postmenopausal women without other risk factors for cardiovascular disease.     

Oral ascorbic acid increases plasma oestradiol during postmenopausal hormone replacement therapy

OBJECTIVES: To study the possible interaction between ascorbic acid (AA) and oestradiol (E2) in postmenopausal women on hormone replacement therapy (HRT). METHODS: We studied 25 healthy postmenopausal women who had used percutaneous E2 gel at same dose for 10-12 months, at which time the plasma E2 concentrations were stabilized. The subjects were treated with 1000 mg of AA daily for 3 months and blood samples for assay of AA and E2 were taken at 0, 1 and 3 months. RESULTS: After 1 month of AA treatment, there was an overall increase of 20.8% in E2 levels in the group as a whole. Greater responses were seen in two subgroups. In women with initially the lowest plasma concentrations of AA (<70 micromol/l), there was an increase of 55% in plasma E2 levels which was close to significance (P=0.063). In another subgroup with initially the lowest E2 levels (<0.20 nmol/l) there was a marked and significant increase (from 0.13 to 0.26 nmol/l) in plasma E2 concentrations (P=0.028). CONCLUSIONS: Our results support early findings that AA may interact with oestrogen therapy. Possible interaction of AA with E2 at the level of antioxidation is discussed.     

Intranasal 17beta-estradiol treatment and Vitamin B12, folate and homocysteine in menopause

Objective: This study assessed the effect of intranasal administration of 17β-estradiol (Aerodiol^®) on plasma levels of homocysteine, Vitamin B12 and folate in postmenopausal women.

Methods: In all, 26 symptomatic postmenopausal women who had undergone hysterectomy and oophorectomy at least 12 months previously participated in this 6-month randomized prospective clinical study. Menopause was determined by serum FSH level >30 μIU/ml and serum estradiol concentration <30 pg/ml. Intranasal 17β-estradiol treatment was given once daily at a standard daily dose of 300 μg to 16 women, and 10 did not receive any treatment.

Results: In the group receiving intranasal 17β-estradiol, mean (±S.D.) plasma homocysteine level decreased significantly from pre-treatment values (from 16.68 ± 4.33 to 14.15 ± 1.18 nmol/ml, p = 0.029) and the mean folate level increased (from 4.11 ± 0.80 to 5.64 ± 1.87 ng/ml, p = 0.012). Vitamin B12 levels showed a tendency towards increasing. In the treated group, significant negative correlations were observed between homocysteine and folate values (r = −0.586, p = 0.017) and between homocysteine and Vitamin B12 values (r = −0.672, p = 0.004). No significant changes were observed in the untreated group.

Conclusion: The reduction in plasma homocysteine levels observed after 6 months’ treatment with intranasal 17β-estradiol may reflect an alteration in folate and Vitamin B12 homeostasis.     

Effect of hormone replacement therapy on lipids in perimenopausal and early postmenopausal women

Objective: To determine the effects of oral sequential hormone replacement therapy (HRT) on lipid-profile in perimenopausal and early postmenopausal women. Methods: We performed a single-center, randomized, placebo-controlled trial. The trial was double blind with respect to 17β-estradiol/desogestrel (17β-E-D) and placebo and open with respect to conjugated estrogens/norgestrel (CEE-N). A total of 125 healthy perimenopausal and early postmenopausal women, aged 43–58 years, were recruited from the general population in Zoetermeer, the Netherlands. The intervention consisted of 6 months treatment with 1.5 mg 17β-estradiol/0.15 mg desogestrel (n=53), 0.625 mg conjugated estrogens/0.15 mg norgestrel (n=36) or placebo (n=36). At baseline, cycle 1, 3 and 6, overnight fasting blood samples were obtained in which lipids were determined. We used linear regression analysis to calculate differences in mean change from baseline in lipids in the active treatment groups compared to placebo. Results: In both treatment groups significant (P<0.05) falls in low-density-lipoprotein (LDL)-cholesterol (17β-E-D: −7.8% and CEE-N: −8.4%) and lipoprotein(a) (17β-E-D: −11.7% and CEE-N: −28.3%) were found compared to placebo. Apolipoprotein A1 (17β-E-D: 6.8% and CEE-N: 7.3%) and HDL-cholesterol (17β-E-D: 6.4% and CEE-N: 8.0%) significantly increased compared to placebo. No significant changes were found in the other lipids. Mean changes from baseline in total cholesterol, LDL-cholesterol and apolipoprotein B were significantly more pronounced in postmenopausal women compared to perimenopausal women, adjustment for age-differences did not change the results. Conclusion: Treatment of perimenopausal and early postmenopausal women with 17β-E-D or CEE-N changes their lipid-profile in a potentially anti-atherogenic direction. Changes appear to be more pronounced in postmenopausal women compared to perimenopausal women.     

Absorption of percutaneous oestradiol in postmenopausal women

Seven postmenopausal women have been treated daily with 3 mg oestradiol percutaneously applied upon the skin. Blood samples were drawn at 8-h intervals during a 4-day period and on days 5, 7 and 9 from the beginning of the treatment. Plasma oestradiol (E2), oestrone (E1), follicle stimulating hormone (FSH) and luteinizing hormone (LH) were determined by radioimmunoassay on these samples.The plasma E2 level was significantly increased at the 12th hour (73 ± 17 pg/ml) but the maximal plasma concentration was obtained only at the third day of treatment (110 ± 24 pg/ml). Thereafter the mean plasma concentration was more stable.Increments in E1 were smaller and the plasma $\text{E2}\text{E1}$ ratio was 1.51.Plasma FSH and LH did not change significantly during the course of the treatment.Thus the percutaneous administration of E2 appears to be an effective and safe method of delivering E2 into the circulation, and mimicking the physiologic condition. The advantages of this method are discussed.     

Ethanolic extracts of black cohosh (Actaea racemosa) inhibit growth and oestradiol synthesis from oestrone sulphate in breast cancer cells

Extracts of black cohosh (Actaea racemosa) and soy are used as ‘natural’ alternatives to conventional hormone replacement therapy (HRT) and there is some evidence that soy may protect against breast cancer by inhibiting the production of active oestrogens. This study compares the action of ethanolic extracts of black cohosh (BCE) and genistein on growth and enzyme activity in MCF-7 and MDA-MB-123 breast cancer cells. BCE inhibited growth at the two highest doses tested, i.e. 50 and 100 μg/ml, whilst genistein stimulated growth in the oestrogen receptor positive (ER⁺) MCF-7 cells, but at high doses it inhibited growth in both cell lines. BCE did not affect the conversion of androstenedione to oestradiol and only the highest doses (50 and 100 μg/ml) significantly inhibited the conversion of oestrone to oestradiol in MDA cells. In contrast, BCE induced a dose-dependent inhibition of the conversion of oestrone sulphate to oestradiol in both cell lines, whilst in human granulosa lutein (GL) cells enzyme activity was only inhibited at the highest dose of BCE. Genistein had no significant effect on enzyme activity in breast cancer cells and like BCE only the highest doses (10 and 50 μM) inhibited enzyme activity in human GL cells. In vivo genistein may have growth stimulatory effects on breast tissue but BCE not only inhibits growth but inhibits the conversion of oestrone sulphate to active oestradiol, considered by some, to be the preferred pathway of oestradiol synthesis in breast tissue.     

Comparison of pharmacokinetic profiles of a 17β-estradiol gel 0.6 mg/g (Gelestra) with a transdermal delivery system (Estraderm TTS 50) in postmenopausal women at steady state

Objectives: to compare the patterns of a 17β-estradiol (E₂) gel containing 0.6 mg/g (1.5 mg E₂ per day, Gelestra); with the transdermal delivery system (Estraderm TTS 50) applied every 3 days over a 14-day period to women in spontaneous or surgical menopause. Methods: a single centre, open, randomised, parallel-group study was conducted. A total number of 33 postmenopausal women were enrolled. In 23 of them the menopause occurred spontaneously, while 10 women were bilaterally ovariectomized. Randomly, the subjects were treated with Estraderm TTS 50 (no. 8) or with Gelestra (no. 14). The pharmacokinetic study of the drugs was performed at the seventh, ninth and 14th day in Gelestra treated women and at the first, third and second day in Estraderm TTS 50 treated women. In fact, the seventh, ninth and 14th day of percutaneous treatment corresponds to the first, third and second day of application of the transdermal system application. Blood samples were taken by each subject at baseline and 1, 2, 3, 4, 8, 12 and 24 h after the gel or transdermal system application. In almost all samples the level of E₂ and estrone (E₁) were evaluated. Statistical analysis was performed by comparing the two groups of treatment. The following parameters were assessed: mean E₂ and E₁ concentrations, E₂ peak serum concentration within interval from 0 to 72 h (C_max), E₂ trough concentration within interval from 0 to 72 h (C_min), area under the E₂ time concentration curve in the interval from 0 to 72 h (AUC_(0–72)), the average E₂ concentration during the measurement interval, calculated by dividing AUC_(0–72) by 72 h (C_av), E₁/E₂ ratio, and percentage fluctuation (%Fluct) which is equal to 100 (C_max−C_min/C_max). Results: there was no significant difference in E₂ C_av between the two treatments. However, significant differences in favour to the gel on the first day (first h) and on third day (72nd h) and in favour to the patch at the second day (48th h) were detected. C_max, E₁/E₂ ratio and AUC_(0–72) were not statistically different, while a significantly higher C_min for the gel was observed. Furthermore, the 90% confidence interval for AUC_(0–72) ratio (0.83–1.10) was within the commonly applied bioequivalence acceptance range (0.80–1.25). The %Fluct was significantly lower for Gelestra than for Estraderm TTS 50. Conclusions: although the mean E₂ and E₁concentrations, C_max, E₁/E₂ ratio and the AUC_(0–72) did not differ between the two E₂ treatments, the Gelestra treatment showed a lower day-to-day variation over the three day application, than the Estraderm TTS 50.     

Changes in the withdrawal bleeding pattern and endometrial histology during 17β-estradiol —dydrogesterone therapy in postmenopausal women: a 2 year prospective study

Objective: To describe changes in the withdrawal bleeding pattern and endometrial histology during a sequential 17β-estradiol —dydrogesterone regimen in postmenopausal women. Design: Open-label, non-comparative, prospective study. Setting: Gynecological outpatient department of a university hospital. Patients: Twenty-seven healthy nonhysterectomized postmenopausal women. Interventions: Continuous micronized 17β-estradiol supplementation, 2 mg daily, and cyclic administration of dydrogesterone, 10 mg daily for the first half of each 28 day treatment cycle. Main Outcome Measures: Changes in the characteristics of the withdrawal bleeding pattern and the endometrial biopsy histology during 2 years of treatment. Results: The initial withdrawal bleeding was comparable to normal menstruation with respect to amount and duration. During the 2 years of treatment the bleeding showed a significant tendency to become shorter with less blood loss. This was mainly the result of the decrease (P < 0.001) in the number of days per cycle with bleeding grade II (normal menstruation). None of the women developed endometrial hyperplasia, and in almost all women the given hormone replacement therapy regimen induced secretory or atrophic changes of the endometrium. Conclusions: This sequential 17β-estradiol —dydrogesterone regimen can be regarded as safe with respect to the prevention of endometrial disease and appeared to foster patient compliance.     

Pharmacokinetics and pharmacodynamic effects of vaginal oestradiol administration from silastic rings in post-menopausal women

Silastic rings releasing approximately 200 μg of 17β -oestradiol per day were inserted into the vaginas of 4 post-menopausal women for one to three 21-day periods. Plasma concentrations of oestrone and oestradiol were analysed by radioimmunoassay. The effect of circulating oestrogens on FSH, LH and sex-hormone binding globulin (SHBG) levels as well as on the endometrium was studied. During the first 24 h of treatment the plasma oestradiol levels were higher than the oestrone levels. But during the following days of the 21-day periods, the levels of the two oestrogens were almost equal, varying between about 100 and 200 pg/ml plasma, a pattern similar to that seen in fertile women. The release of oestradiol from the ring gave stable plasma oestrogen levels. The FSH and LH levels were clearly depressed while the SHBG levels did not change. Characteristics of oestrogen influence were found in endometrial biopsies. The rings were well accepted and could be inserted and removed easily by the women. Absorption of oestradiol from the vagina is good and more complete than after oral administration allowing lower doses to be used for treatment.