Substitution of transdermal estradiol during oral estrogen-progestin therapy in postmenopausal women: effects on hypertriglyceridemia

OBJECTIVE: We investigated effects of changing from oral estrogen to transdermal estradiol on the lipid and lipoprotein profile of postmenopausal women who developed hypertriglyceridemia (serum concentrations exceeding 150 mg/dL) during estrogen-progestin therapy. DESIGN: Sixty-one postmenopausal Japanese women receiving 0.625 mg of conjugated equine estrogen plus 2.5 mg of medroxyprogesterone acetate daily for 12 months had developed serum triglyceride concentrations exceeding 150 mg/dL after 12 months of treatment. Thirty-six of them, chosen randomly for study, were assigned at random to either a group that continued this oral regimen or another that changed to transdermal estradiol while continuing 2.5 mg of oral medroxyprogesterone acetate for the next 3 months (n = 18 for each). Blood lipids were compared between groups. RESULTS: Serum concentrations of triglyceride and very-low-density lipoprotein triglyceride decreased significantly after changing to transdermal estradiol (triglyceride, from 226.0 +/- 43.9 to 110.5 +/- 44.1 mg/dL, P < 0.01). No changes were seen in concentrations of low-density lipoprotein cholesterol or high-density lipoprotein cholesterol. CONCLUSION: Changing to transdermal estradiol may improve triglyceride metabolism in women who developed hypertriglyceridemia during oral estrogen-progestin therapy, with minimal effect on cholesterol profiles.     

Effects of ultralow-dose transdermal estradiol on postmenopausal symptoms in women aged 60 to 80 years

OBJECTIVE: To investigate the effect of ultralow-dose transdermal estradiol on postmenopausal symptoms and side effects in a cohort of largely asymptomatic postmenopausal women aged 60 to 80 years. DESIGN: This secondary analysis used data from the UltraLow-dose Transdermal estRogen Assessment trial, a randomized, placebo-controlled, double-blind trial in postmenopausal women to determine the skeletal effects and safety of ultralow-dose transdermal estradiol. Four hundred seventeen postmenopausal women, aged 60 to 80 years, were randomly assigned to receive either unopposed transdermal estradiol at 0.014 mg/d (n = 208) or placebo (n = 209). Participants were queried at each clinic visit about postmenopausal symptoms and side effects purported to be associated with estrogen therapy using a standardized questionnaire. RESULTS: At baseline, 16% of women reported hot flashes, 32% reported vaginal dryness, and 35% reported trouble sleeping. Women who received ultralow-dose estradiol were no more likely to report improvement of hot flashes, vaginal dryness, or sleep difficulties than those who received placebo. Treatment with ultralow-dose estradiol did not cause breast tenderness, uterine bleeding, or other symptoms often attributed to estrogen, but vaginal discharge was more common in women who received estradiol compared with those who received placebo. CONCLUSION: In this population of older, largely asymptomatic women, ultralow-dose transdermal estradiol did not improve postmenopausal symptoms and did not cause side effects other than vaginal discharge. Further study is needed to determine whether this dose of transdermal estradiol is effective in treating symptoms of postmenopause in younger, more symptomatic women.     

Effect of estradiol versus estradiol and testosterone on brain-activation patterns in postmenopausal women

OBJECTIVE: To determine the effect of estradiol and testosterone on brain-activation patterns in surgically postmenopausal women viewing erotic video clips using functional magnetic resonance imaging. DESIGN: Six women, who had undergone a bilateral oophorectomy and hysterectomy for benign disease, viewed erotic and neutral videos during functional magnetic resonance imaging while not on hormone therapy, while on estradiol therapy, and while on estradiol and testosterone therapy. Five similarly aged premenopausal women viewed the same videos. Areas of brain activation between the functional magnetic resonance imaging scans of both groups of women were compared with determine whether agonadal serum levels of sex hormones and administration of estradiol and testosterone impacted brain patterns of sexual arousal. RESULTS: When compared with premenopausal women, untreated postmenopausal women had significantly decreased areas of brain activation during both erotic and neutral stimulations. Administration of estradiol increased global brain-activation patterns during both visual stimulations, with erotic video viewing causing a limited increase in limbic system activation. Combined estradiol and testosterone therapy was associated with a greater activation of the central nervous system, with more limbic system activated during the erotic video. Brain-activation patterns of the postmenopausal women were similar to the premenopausal group only during the estradiol and testosterone treatment phase. CONCLUSIONS: Agonadal serum hormone levels result in globally decreased brain-activation patterns in postmenopausal women while viewing neutral and erotic videos. Administration of both estradiol and testosterone increase global brain activation, and both sex steroids are independently associated with enhanced limbic system response during erotic visual stimulation.     

Comparative bioavailability study of an once-a-week matrix versus a twice-a-week reservoir transdermal estradiol delivery systems in postmenopausal women

An open-label, randomised, crossover study was conducted with in healthy postmenopausal women to compare the relative bioavailability of a matrix transdermal estradiol delivery system worn for 7 consecutive days, versus a reservoir transdermal patch worn for 4 days followed by its immediate replacement by another patch worn for further 3 consecutive days. There was a minimum 7-day washout period between the two study periods. Both systems were labelled to release approximately 50 μg/day of estradiol. Twenty-six subjects were evaluated with regard to estradiol serum levels. Blood samples were taken immediately before and at regular intervals until 192 h after the initiation of each study treatment (patch application) and assayed for estradiol. There was no difference between the patches with regard to C_max. Based on the relative bioavailability, one matrix patch proved to be bioequivalent to two reservoir patches worn consecutively for 7 days. These results demonstrate the ability of one matrix patch to deliver consistent therapeutic levels of estradiol over a 7-day period.     

Efficacy and tolerability of a new 7-day transdermal estradiol patch versus placebo in hysterectomized women with postmenopausal complaints

OBJECTIVES: To investigate the efficacy and tolerability of a continuously applied 7-day-Estradiol patch (Fem7, Merck KGaA, Germany) delivering 50 microg estradiol per day in the treatment of hysterectomized women with postmenopausal complaints compared with placebo. DESIGN: A multicentre, randomized, double-blind study with an initial screening phase (phase I), a 3-month double-blind placebo-controlled phase (phase II) and a 3-month open follow-up phase (phase III). METHODS: 186 patients were randomized for a 3-cycle placebo-controlled study followed by a 3-cycle open follow-up (total duration; 6 months). The changes in Kupperman Index (primary efficacy variable), hot flushes and urogenital symptom score were studied from baseline to the end of the study. In addition, skin tolerability was assessed and patients were also asked to grade the subjective acceptance of therapy. RESULTS: A reduction in Kupperman Index was observed in both groups, and at each cycle of the placebo-controlled treatment phase the 7-day-Estradiol patch was superior compared with placebo (last value vs. baseline P = 0.0006). From the second treatment week onwards a distinct difference was noted in the reduction of hot flushes from baseline between the 7-day-Estradiol patch group and the placebo group. The difference between the groups was statistically significant for each cycle and at the end of the controlled treatment phase (mean weekly hot flush reduction at the end of the placebo-controlled treatment phase: -32.5 for the 7-day-Estradiol patch vs. -22.0 for placebo, P = 0.0025). The efficacy of the 7-day-Estradiol patch within the application period did not show any difference between days 1-3 and 4-7. Subjective acceptance of the 7-day-Estradiol patch was good and 72.4% of patients who took active medication throughout the study were willing to consider continuing its use. CONCLUSIONS: The 7-day-Estradiol patch is well tolerated and provides effective relief of moderate to severe vasomotor symptoms in hysterectomized women, with a rapid onset of action and 7-day duration of therapeutic effect. Although a placebo effect was observed, the 7-day-Estradiol patch significantly reduced hot flushes and other menopausal symptoms throughout the application period.     

Effectiveness of Alora estradiol matrix transdermal delivery system in improving lumbar bone mineral density in healthy,postmenopausal women

OBJECTIVE: To determine the lowest effective dose of an estradiol (E ) matrix-type transdermal delivery system (EMTDS; Alora) for preventing bone loss in postmenopausal women. DESIGN: This double-blind, double-dummy, randomized, placebo-controlled, multicenter study enrolled 355 nonosteoporotic postmenopausal women who had been hysterectomized with or without oophorectomy at least 12 months earlier. Participants were randomly assigned to one of three doses of the EMTDS (0.025, 0.05, or 0.075 mg/day) or placebo administered twice weekly. Lumbar bone mineral density (LBMD) was measured by dual-energy x-ray absorptiometry at screening and after 1 and 2 years of treatment. Safety was assessed at regularly scheduled visits. RESULTS: EMTDS provided statistically significant and clinically meaningful changes in LBMD relative to placebo. At 2 years, LBMD declined from baseline by 0.59% in the placebo group, but it increased from baseline by 1.65% ( = 0.0065), 4.08% ( = 0.0001), and 4.82% ( = 0.0001) in the EMTDS 0.025, 0.05, and 0.075 mg/day groups, respectively. The corresponding responder rates (defined as no change or increase in LBMD at endpoint) were 39.7% for placebo, 59.6%, 79.3%, and 83.9% in the EMTDS 0.025, 0.05, and 0.075 mg/day groups, respectively. Mean serum E concentrations were proportional to the dose of the E transdermal system and did not accumulate over the course of the study. Adverse events were generally comparable across treatment groups, with the majority being mild or moderate in severity and unrelated to study medication. Mammogram findings and other safety assessments were also comparable across groups and did not reveal any safety concerns with 2-y transdermal E treatment. CONCLUSIONS: The EMTDS (Alora) administered twice weekly improves lumbar bone mineral density in healthy postmenopausal women, with the benefit of treatment evident by 1 year. The lowest effective dose is 0.025 mg/day.     

Comparison of transdermal estradiol and tibolone for the treatment of oophorectomized women with deep residual endometriosis

Study objective: To compare the effect of HRT with transdermal estradiol and that of treatment with tibolone in post-menopausal women with residual endometriosis. Materials and Methods: 21 women with residual pelvic endometriosis after bilateral oophorectomy with or without hysterectomy were enrolled in the study and were randomized to HRT with transdermal estradiol 50 mg twice weekly (n=10) associated with cyclic medroxyprogesterone acetate 10 mg daily in women who preserved uterus, and to treatment with tibolone 2.5 mg administered orally once a day (n=11). The duration of both treatments was scheduled to last at least 12 months. Residual endometriosis was located in the bowel wall in four patients, in the rectovaginal septum in six and deeply in the retroperitoneal pelvic space in six. All women were symptomatic before oophorectomy. Results: All the women were followed for 12 months. No patient suspended therapy because of side effects. Four patients of the estradiol group experienced moderate pelvic pain during treatment compared with only one patient in the tibolone group. One patient in the estradiol group reported severe dyspareunia. Conclusion: Although our series is very small, it seems that tibolone may be a safe hormonal treatment for post-menopausal women with residual endometriosis.     

Acute effect of intranasal estrogen on cerebral and cerebellar perfusion in postmenopausal women

OBJECTIVES: Estrogen action in the brain influences many neurochemical processes. The aim of the study was to evaluate the acute effect of intranasal 17beta-estradiol on cerebral and cerebellar perfusion in postmenopausal women. METHODS: The study group included 24 healthy postmenopausal women who had been in natural menopause for at least 1 year (mean age: 47.38+/-5.9 years). We conducted an experimental, randomized, placebo-controlled, cross-over, double-blind study. Cerebral and cerebellar perfusion was measured after placebo (saline serum physiologic) or intranasal 17beta-estradiol administration by Single Photon Emission Computed Tomography (SPECT) using technetium-99m-hexamethylpropylene amine oxime (Tc99m-HMPAO). Regions of interest (ROIs) were drawn manually. Cerebral and cerebellar perfusions were calculated for each ROI using average number of counts per pixel. Semiquantitative analysis was performed in bilateral frontal, temporal, parietal and occipital lobes, thalamus, putamen, hippocampus, amygdala, caudate nuclei, cerebellar region, anterior/posterior of cingulate gyrus and pons. RESULTS: After intranasal 17beta-estradiol administration, SPECT study revealed significant increases in cerebral and cerebellar perfusion compared to placebo measurements in all studied slices (p<0.05). There was a positive correlation between serum estrogen levels after 17beta-estradiol and cerebral and cerebellar perfusion. CONCLUSIONS: Administration of single dose intranasal 17beta-estradiol increases cerebral and cerebellar perfusions in healthy postmenopausal women.     

Low dose transdermal estradiol/norethisterone acetate treatment over 2 years does not cause endometrial proliferation in postmenopausal women

OBJECTIVE: We investigated the effects of 2-year transdermal continuous combined estradiol (0.025 mg/day) and norethisterone acetate (0.125 mg/day) (Estragest TTS) on bleeding and on the endometrium. DESIGN: This double-blind, randomized, multicenter, parallel, 1-year trial enrolled 266 healthy women at least 2 years past menopause with intact uteri. Patients received a transdermal patch delivering either 0.025 mg estradiol and 0.125 mg norethisterone acetate daily or placebo. Of the 266 women initially included, 135 (96 Estragest TTS, 39 placebo) completed a second year open follow-up, where all women had the estradiol/norethisterone patch. Endometrial biopsies were performed at weeks 0, 48 (n = 171), and 96 (n =109). Effects on endometrial morphology and uterine bleeding were studied. RESULTS: The overall incidence of endometrial hyperplasia after treatment with the estradiol/norethisterone acetate patch for one year was 0.8% with only one case of atypical hyperplasia. There were no clinically significant changes in endometrial thickness in either treatment group. The proportion of bleed-free patients with the estradiol/norethisterone acetate transdermal system increased from 55% in cycles 1-3 to 83% in cycles 10-12. By the 12th cycle, 92% of patients receiving estradiol/norethisterone acetate patches were bleed-free. No additional hyperplasia was seen during the second year follow-up. CONCLUSIONS: A continuous combined transdermal patch delivering 0.025 mg estradiol/day and 0.125 mg norethisterone acetate/day provided good endometrial protection. The dose maintained a consistently high rate of amenorrhea in postmenopausal women.     

Influence of transdermal estradiol in the regulation of leptin levels of postmenopausal women: a double-blind, placebo-controlled study.

OBJECTIVE: To investigate whether the administration of transdermal estradiol is capable of modifying circulating levels of leptin. DESIGN: Forty postmenopausal women randomly received in a double-blind fashion, a transdermal patch containing either placebo or estradiol (50 microg/day). After 2 months of treatment, they were switched to the alternate treatment for another 2 months. Leptin levels were measured at the end of the placebo and estradiol administration. In a subset of 28 women an evaluation of body composition via bioelectrical impedance and an oral glucose tolerance test (OGTT; 75 g) were also performed at the end of the placebo and estradiol administration. Glucose, insulin, and leptin levels were measured in all OGTT samples. RESULTS: Leptin levels were related directly to body mass index (BMI), fat mass, and insulin, and inversely related to lean mass. In comparison to placebo, transdermal estradiol increased estradiol (from 77.8 +/- 8.4 pmol/l to 183.1 +/- 20.9 pmol/l; p < 0.0001) but did not significantly modify leptin (19.1 +/- 2.4 microg/l vs. 18.6 +/- 2 microg/l) or BMI. Estradiol did not modify fat mass or lean mass, significantly increased intracellular water (31.1 +/- 0.7% vs. 37.2 +/- 2.3%, p < 0.05), and decreased extracellular water (40.5 +/- 0.7% vs. 36.3 +/- 1.7%; p < 0.04). Leptin did not increase during OGTT, but a significant decrease, linearly related to BMI ( r = 0.519; p = 0.0189), was observed at the end of the test. CONCLUSIONS: Low doses of transdermal estradiol exert no influence on fasting leptin levels or BMI. The possibility that different doses of estradiol exert a more pronounced effect on circulating leptin needs to be addressed in comparative studies.     

Markedly elevated levels of estrone sulfate after long-term oral, but not transdermal, administration of estradiol in postmenopausal women

OBJECTIVE: To compare serum estrone sulfate (E1S) levels in postmenopausal women during long-term treatment with commonly prescribed doses of oral and transdermal estradiol (E2). DESIGN: A retrospective study performed in a University setting in the United States involving 33 healthy postmenopausal women. Two groups of postmenopausal women were studied: group 1 (n = 10) received 1 mg oral micronized E2 daily for 16 months; blood was drawn at 0, 7, and 15 months. Group 2 (n = 23) was randomized into three subgroups. Two of the subgroups (n = 8; n = 7) received E2 delivered at a rate of 0.05 mg/day and 0.1 mg/day, respectively, by transdermal patch, changed twice weekly; the third subgroup received a placebo (without E2) patch for 9 continuous months. Blood samples were drawn at 0, 6, and 9 months. Serum E1S and E2 were quantified by specific radioimmunoassays. Statistical analysis was performed by analysis of variance. RESULTS: After oral E2 treatment, E1S levels increased significantly (p < 0.01) from baseline, reaching an average level of 38.8 ng/mL at 15 months. After transdermal E2 treatment, E1S levels increased significantly, yet to a much lesser extent, reaching levels of 1.8 ng/mL and 3.2 ng/mL after 9 months of treatment with the 0.05 mg/day and 0.1 mg/day patches, respectively. CONCLUSIONS: Markedly elevated levels of E1S were found after long-term oral estrogen treatment. In comparison to the increase in E1S levels after long-term oral estrogen treatment, there was only a small increase in E1S levels after transdermal E2 therapy. This difference may be attributed to the higher dosage of oral E2 that is required because of the low bioavailability compared with the transdermal dosages.     

Comparison between 1 year oral and transdermal oestradiol and sequential norethisterone acetate on circulating concentrations of leptin in postmenopausal women

BACKGROUND: Oral and transdermal postmenopausal hormone replacement therapy (HRT) affects lipid and glucose metabolism differently, which is of significance in the release of leptin by adipocytes. Moreover, oestrogen and progesterone can stimulate leptin secretion in women of reproductive age. Therefore, we compared the effects of oral and transdermal oestrogen plus progestin regimen on plasma leptin in 38 healthy postmenopausal women with normal body mass index (BMI), who wished to use HRT to control incapacitating climacteric symptoms. METHODS: The women were randomized to treatment with oral HRT (2 mg oestradiol on days 1--12, 2 mg oestradiol plus 1 mg norethisterone acetate (NETA) on days 13--22, and 1 mg oestradiol on days 23--28, n = 19), or with transdermal HRT (50 microg/day of oestradiol on days 1--13, and 50 microg oestradiol plus 250 microg/day NETA on days 14--28, n = 19) for 1 year. Plasma samples were collected before and at oestradiol + NETA phase after 2, 6 and 12 months treatment and were assayed for leptin. RESULTS: The baseline leptin, ranging from 3.3 to 34.9 microg/l, was significantly associated with BMI (r = 0.78, P < 0.0001 ), but showed no difference between women in oral HRT (geometric mean 13.9 microg/l, 95% confidence interval (CI) 10.1--17.6 microg/l) or transdermal HRT group (geometric mean 12.0 microg/l, 95% CI 9.7--14.3 microg/l). Neither oral nor transdermal oestradiol + NETA caused any significant changes in plasma leptin (or BMI) after 2, 6, or 12 months of treatment. CONCLUSION: Leptin is an unsuitable factor to detect oestradiol + NETA-induced metabolic changes in postmenopausal women.     

A comparison of effects of sequential transdermal administration versus oral administration of estradiol plus norethisterone acetate on serum NO levels in postmenopausal women

AIM: To compare the effects of sequential transdermal administration versus oral administration of estradiol plus NETA on serum nitric oxide (NO) levels in postmenopausal women (PMW). MATERIALS AND METHODS: Eighty postmenopausal subjects without any prior hormone replacement therapy (HRT) usage were enrolled in this study. All participants were healthy, ambulatory, non-smoker and had similar life styles with dietary habits. HRT was given to participants according to desired HRT administration, in group A (n=50); oral estradiol hemi-hydrate (2 mg)/norethisterone acetate (1 mg), and in group B (n=30); transdermal combined patch comprising estradiol (0.05 mg) alone and estradiol (0.05 mg)/norethisterone acetate (0.25 mg), were given sequential for 12 months. Serum NO levels were studied using Total Oxide Assay Kit (Assay Designs, Inc.) according to manufacturer's instructions prior to and after 12 months from the HRT treatment. RESULTS: The mean serum NO levels prior to the HRT in groups A and B was 0.48+/-0.46 (range, 0.27-0.76 nmol/mL) nmol/mL and 0.47+/-0.48 nmol/mL (range, 0.29-0.693 nmol/mL) (p>0.05). The mean serum NO levels after the HRT in groups A and B was 0.53+/-0.33 nmol/mL (range, 0.29-2.10 nmol/mL) and 2.91+/-0.50 nmol/mL (range, 2.10-3.67 nmol/mL) (p<0.05). A significant difference was found between mean serum NO levels prior to and after the treatment in group B (p<0.05). CONCLUSIONS: Transdermal sequential combined HRT with estradiol hemi-hydrate/NETA was found to be superior to sequential combined oral HRT in increasing serum NO levels.     

Impact of hormone replacement therapy on endogenous estradiol metabolism in postmenopausal women

OBJECTIVES: Changes in estradiol metabolism may play a role in the pathophysiology of different diseases, of special interest being an increase in D-ring over A-ring metabolites for the risk of breast cancer. In the present work we investigated the effect of exogenous estradiol therapy on endogenous estradiol metabolism in postmenopausal women. METHODS: Three different studies were carried out in 126 women: in study A the women were treated for 4 weeks either with oral or with transdermal 17beta-estradiol, in study B for 4 weeks with oral or transdermal 17beta-estradiol sequentially combined with oral or transdermal norethisterone acetate, and in study C for 12 weeks either with oral 17beta-estradiol or with an oral continuous combination of 17beta-estradiol with the new progestin dienogest. As main representatives of the A- and D-ring metabolism, 2-hydroxyestrone (2-OHE1) and 16 alpha-hydroxyestrone (16-OHE1), respectively, were measured in 8 h night urine using enzyme immunoassay technique. RESULTS: Oral estradiol treatment resulted in a significant higher excretion of estradiol metabolites compared to transdermal treatment. Neither oral nor transdermal estradiol induced a significant change in the ratio of 16-OHE1 to 2-OHE1. The addition of oral or transdermal norethisterone acetate to estradiol did not alter on average the endogenous estradiol metabolism, although in individual patients a significant increase in 16-OHE1 metabolism was observed only with oral norethisterone. The continuous oral addition of dienogest did not lead to any significant change in estradiol metabolism. CONCLUSIONS: These results indicate that oral estradiol replacement therapy enhances the quantity of circulating estradiol metabolites. This may have a more negative impact on estrogenic target cells as compared to transdermal application. Progestin addition to estradiol replacement therapy seems to have no major impact on endogenous estradiol metabolism. Further studies, however, are necessary to evaluate the progestin effect in possible pre-disposed patients.     

Long-term effects of transdermal and oral estrogens on serum lipids and lipoproteins in postmenopausal women

The transdermal and oral administration of estrogens for one year were compared with respect to the effects on lipid metabolism. Eighty-one postmenopausal women (1.5-3 years after menopause) were randomly divided into three groups. The first two groups received sequential estrogen treatment with either transdermal estradiol (Estraderm TTS, Ciba Geigy; 50 μg/day; 24 women) or 0.625 mg/day conjugated estrogens (Premarin, Wyeth; 20 subjects), respectively. In both groups medroxyprogesterone (10 mg/day per os) was added for 12 days of each cycle. Thirty-five subjects served as control group without therapy. No significant changes in the lipid profile was observed in control subjects after 1 year of follow-up. Serum triglycerides decreased significantly (-10.9 ± 26% S.D.; P < 0.05) in transdermal treated women, whereas it slightly rose in oral estrogen group. Comparable significant decreases in total and low density lipoprotein (LDL) cholesterol (mean range -6.5/-18.0%) were observed in women on estrogen replacement therapy. High density lipoprotein (HDL) cholesterol significantly diminished in transdermal estradiol group, but it rose slightly in the oral estrogen group. Thus the fraction of HDL cholesterol over LDL cholesterol did not change in the transdermal group whereas it significantly rose in subjects treated with oral estrogens. It remains to be established to what extent these differences on lipid metabolism are relevant for the prevention of cardiovascular diseases.