Estradiol absorption from vaginal tablets in postmenopausal women.

OBJECTIVE: To evaluate absorption of estradiol (E2) and compare two low doses of 17 beta-E2 (25 microgram and 10 microgram) in postmenopausal women with atrophic vaginitis. METHODS: In a double-masked, randomized, parallel-group study, 58 postmenopausal women were treated with 25 microgram or 10 microgram of 17 beta-E2 for 12 weeks. We report data for 42 eligible subjects who had serum E2 concentrations below 20 pg/mL at baseline and complete data available at the baseline visit (30 minutes before tablet insertion) and weeks 2 and 12. Serum E2 and FSH concentrations were measured at specified intervals. The area under the curve, maximal concentration, and time to maximal concentration were measured for serum E2 concentrations. Maturation values of vaginal epithelial cells were assessed as indicators of change in vaginal epithelium condition in response to treatment. RESULTS: After 12 weeks of treatment, the area under the curve, maximal and average over 24-hour E2 concentration were higher in the 25-microgram (563 pg. hour/mL, 49 and 23 pg/mL) than in the 10-microgram (264 pg. hour/mL, 22 and 11 pg/mL) group. Seventy-four percent in the 25-microgram and 96% in the 10-microgram groups had low systemic absorption of E2, that is, area under the curve (0-24 hour) less than 500 pg/mL. All but three women who received 25 microgram had mean FSH levels below 35 mIU/mL. CONCLUSION: Treatment with 25 or 10 microgram of 17 beta-E2 vaginal tablets resulted in low absorption of estrogen without systemic effects often associated with hormone replacement therapy. After 12 weeks of therapy for atrophic vaginitis, absorption patterns remained consistent, and women did not have accumulations of circulating E2.

Effects of estrogen/androgen therapy on bone mineral density parameters.

Although estrogen's efficacy in reversing loss of bone mineral density (BMD) has been extensively documented, the role of androgens in preserving and restoring BMD is less well understood. Estrogen/androgen (E/A) therapy is especially important for surgically menopausal women. This population group experiences marked bone loss in response to the dramatic decline in ovarian hormones. The resulting hormonal profile differs significantly from that of naturally menopausal women. For surgically menopausal women, the relation of estrogens, androgens and sex hormone binding globulin (SHBG) is of special concern, as the interrelation between these hormones ultimately may reduce hormonal bioavailability. This paper reviews the relation of bone metabolism to ovarian hormones and the mechanics of BMD loss as well as the tools available to clinicians to assess bone loss in menopausal women. It further discusses androgen excess in women with polycystic ovary syndrome. Currently available hormonal regimens to preserve bone are described, including estrogen-only therapy, E/A therapy, tibolone and estrogen-progestogen therapy.

Suppression of vasomotor and vulvovaginal symptoms with continuous oral 17beta-estradiol.

OBJECTIVES: To evaluate the efficacy and safety of different doses of 173-estradiol for the treatment of vasomotor and vulvovaginal symptoms. DESIGN: This was a randomized, double-blind, multicenter, parallel-group study. One hundred forty-five subjects, including naturally postmenopausal women aged 40-60 (who had not experienced menses for at least 12 months), women who had undergone hysterectomy, and women aged 25-60 who had undergone bilateral oophorectomy with or without hysterectomy were studied. Either placebo or 17beta-estradiol (1 mg or 0.5 mg) was given orally every day for 12 weeks, and vasomotor symptoms and vaginal epithelial cytology were evaluated. RESULTS: There were significant differences between placebo and the active treatments in the percentage change from baseline in the number of hot flushes (all hot flushes, 1 mg vs. placebo, p < 0.00 1; 0.5 mg vs. placebo, p = 0.007), with a more substantial proportion of subjects responding in the 1-mg group (mean change in mean number of hot flushes of 83.2%). Both doses were also more effective than placebo in increasing the proportion of mature vaginal cells (end-of-treatment mean values of 0%, 78.5%, and 21.5% for parabasal, intermediate, and superficial cells, respectively, in the 1-mg group; mean values of 0.3%, 80.8%, and 18.9% in the 0.5-mg group; and mean values of 15.2%, 74.7%, and 10.2% in the placebo group). The proportion of subjects reporting no vaginal dryness was greatest in the 1-mg group (mean percentage of days without dryness of 86.1% at weeks 9-12). CONCLUSIONS: For the relief of vasomotor and vulvovaginal symptoms, 17beta-estradiol I mg is effective and has an excellent safety profile.

The effect of site of application on the transcutaneous absorption of 17-beta estradiol from a transdermal delivery system (Climara).

OBJECTIVE: The effect of site of application on 17-beta estradiol bioavailability was assessed in an open-label, randomized, crossover study of a once-weekly transdermal estradiol patch (Climara). DESIGN: After placement of a transdermal patch delivering 0.1 mg/day of estradiol on either the buttocks or abdomen, serial plasma samples were obtained over 7 days and for the immediate 24 h after patch removal. Plasma estradiol concentrations were used to estimate pharmacokinetic parameters for the rate and extent of absorption between the two sites. RESULTS: Plasma estradiol concentrations were sustained at premenopausal levels over the week in most subjects. After application on the buttock, mean peak plasma concentration (Cmax) was 125.1% and mean relative bioavailability (AUC(0-168)) was 117.2% of that from the abdomen site. CONCLUSIONS: In summary, the buttocks seem to be an acceptable site for the application for this once-weekly 17-beta estradiol transdermal delivery system. Because the extent of absorption was significantly more for buttock than for abdomen application, this application site may provide an advantage in women who experience menopausal symptoms at the end of the week.

Initial 17beta-estradiol dose for treating vasomotor symptoms.

OBJECTIVE: To compare the efficacy of different doses of 17beta-estradiol (E2) for relief of vasomotor symptoms in menopausal women. METHODS: This was a randomized, double-masked, placebo-controlled, 12-week study in which 333 menopausal women with moderate or severe hot flushes were assigned to treatment with 0.25 mg, 0.5 mg, 1 mg, or 2 mg oral micronized 17beta-E2, or placebo. The number and severity of hot flushes were recorded daily. RESULTS: There was a significant linear correlation between increased dosage of 17beta-E2 and decreased moderate to severe hot flushes per week (P <.001). Rapid reduction in moderate to severe hot flushes was only achieved with 1 and 2 mg, showing a significant difference from placebo at week 4 (P <.05). At week 4, half the women on placebo had reduced moderate to severe hot flushes of at least 52%; the corresponding figures were 56%, 69%, 86%, and 91% for 0.25, 0.5, 1, and 2 mg, respectively. At week 12, all doses except 0.25 mg were significantly better than placebo for reducing moderate to severe hot flushes (P <.001). Although there were no significant differences, twice as many women in the 2-mg group discontinued treatment due to adverse events, compared with the placebo group. CONCLUSION: Oral micronized 17beta-E2 showed a dose-response effect for reducing moderate and severe hot flushes in menopausal women. 17beta-E2 1 mg appeared to be the most useful initial dose.

Efficacy of continuous sequential transdermal estradiol and norethindrone acetate in relieving vasomotor symptoms associated with menopause.

OBJECTIVE: This study was undertaken to evaluate the efficacy and tolerability of a combination estradiol plus norethindrone acetate transdermal delivery system given in a continuous sequential regimen with transdermal estradiol versus placebo in the treatment of vasomotor symptoms of menopause. STUDY DESIGN: This was a 12-week double-blind trial of 220 healthy postmenopausal women with > or = 8 moderate to severe hot flushes and sweating episodes per day. Women were randomly assigned to wear transdermal placebo patches or a transdermal patch releasing 50 microg/d 17beta-estradiol alone (Vivelle) for days 1 to 14 of each cycle and a combination patch releasing 50 microg/d 17beta-estradiol plus 1 of 3 dosage levels (140, 250, or 400 microg/d) of norethindrone acetate (CombiPatch) for days 15 through 28. RESULTS: There was a significant (P <.001) reduction by the second week in the mean number of daily hot flushes from baseline to end point with all 3 doses of estradiol plus norethindrone acetate compared with placebo. Significant (P <.001) reductions in the mean intensity of hot flushes and sweating were also noted with estradiol plus norethindrone acetate compared with placebo. The incidences of adverse events with all 3 doses of estradiol plus norethindrone acetate and with placebo were comparable. CONCLUSION: An estradiol plus norethindrone acetate transdermal delivery system administered in a continuous sequential regimen with transdermal estradiol was well tolerated and effective for the treatment of moderate to severe vasomotor symptoms in postmenopausal women.

A two-year, double-blind comparison of estrogen-androgen and conjugated estrogens in surgically menopausal women. Effects on bone mineral density, symptoms and lipid profiles.

OBJECTIVE: To compare the effects of two doses of conjugated equine estrogen (CEE) and two of esterified estrogen plus methyltestosterone (E + A) in surgically menopausal women. STUDY DESIGN: A two-year, parallel-group, double-blind study of 311 women who were randomly assigned to one of four regimens: (1) CEE, 0.625 mg/d; (2) CEE, 1.25 mg/d; (3) esterified estrogens, 0.625 mg, + methyltestosterone, 1.25 mg/d; or (4) esterified estrogens, 1.25, + methyltestosterone, 2.5 mg/d. Study parameters were symptoms, lipids, bone mineral density, side effects and safety. RESULTS: All treatments prevented loss of bone in the spine and hip. The higher E + A dose increased spine and hip BMD more than other treatments (P < .002). All treatments improved menopausal symptoms, with non-significantly greater improvements in well-being and sexual interest in the E + A groups. Similar and significant decreases in low-density lipoprotein were observed in all groups, but high-density lipoprotein and triglycerides were increased only in the unopposed estrogen groups (P < .05). Hirsutism was uncommon and similar in all groups at two years. Discontinuation rates and reasons for withdrawal from the study were similar in both groups. No clinically significant side effects or laboratory test abnormalities were seen. CONCLUSION: As compared to estrogen alone, E + A significantly improved BMD and was well tolerated in surgically menopausal women.

Clinical experience with a 7-day estrogen patch: principles and practice.

In the future, hormone replacement therapy (HRT) is likely to become of increasing importance, not only to control short-term climacteric symptoms, but also to protect postmenopausal women from the increasing risk of cardiovascular disease, osteoporosis and other conditions that accompany ovarian failure. This paper reviews the principles and practice associated with HRT, focusing on clinical experience with a new 7-day estrogen matrix patch (Climara). Results from two 11-week placebo-controlled studies, which compared the 7-day patch at two dose levels with 0.625-mg/day oral conjugated equine estrogen, found that both the 0.5- and 0.1-mg estradiol/day patches had a positive effect on climacteric symptoms. Tolerance was good and similar for both patches. Separate studies of skin irritation and adhesion revealed that the 7-day patch was well tolerated and that, although irritation was similar to that associated with Estraderm, adhesion was superior with the 7-day patch. Data on absorption of estradiol from different skin sites indicate that absorption is higher and more consistent from the buttock than from the abdomen, suggesting that choice of application site may require further investigation.

Effects of group- versus home-based exercise in the treatment of obesity.

This study examined the effects of 2 aerobic exercise regimens on exercise participation, fitness, eating patterns, treatment adherence, and weight change in 49 obese women undergoing a year-long behavioral weight loss program. Participants were assigned randomly to weight loss treatment plus either group- or home-based exercise. All participants were instructed to complete a moderate-intensity walking program (30 min/day, 5 days/week). Group exercise participants were provided with 3 supervised group exercise sessions per week for the first 26 weeks and with 2 sessions per week thereafter. Home exercise participants were instructed to complete all exercise in their home environment. After 6 months, both conditions displayed significant improvements in exercise participation, fitness, eating patterns, and weight loss. At 12 months, the home-based program showed superior performance to the group condition in exercise participation and treatment adherence; at 15 months, participants in the home program demonstrated significantly greater weight losses than those in the group program.

Hormone replacement therapy in postmenopausal women: urinary N-telopeptide of type I collagen monitors therapeutic effect and predicts response of bone mineral density.

PURPOSE: To assess the ability of the urinary N-telopeptide of type I collagen (NTx) to monitor and predict therapeutic effects of hormone replacement therapy (HRT) in postmenopausal women. PATIENTS AND METHODS: To assess the relationship between baseline or change in NTx (predictive variable), and change in lumbar and hip bone mineral density (BMD; outcome variable), we conducted a 2-year randomized controlled study at academic university and private practice medical centers in 236 healthy women 1 to 3 years postmenopausal; 227 women completed the study. Women received estrogen plus progesterone plus calcium (treated group) or calcium alone (control group). RESULTS: In the treated group NTx significantly (P < 0.0001) decreased, and spine and hip BMD significantly (P < 0.00001 and P < 0.005, respectively) increased; in the control group NTx did not change but BMD decreased significantly (P < 0.01). Subjects in the highest quartiles for baseline NTx (67 to 188 units) or decreasing NTx (-66% to -87%) through 6 months demonstrated the greatest gain in BMD in response to HRT (P < 0.05 and P < 0.005). For every increase of 30 units in baseline NTx the odds of gain in BMD in response to HRT increased by a factor of 5.0 (95% confidence interval [CI] 1.9 to 13.3); for every 30% decrease in NTx through 6 months, the odds of gaining BMD in response to HRT increased by a factor of 2.6 (95% CI 1.6 to 4.4). In the control group an increase of 30 units in mean NTx across the study indicated a higher odds of losing BMD by a factor of 3.2 (95% CI 1.6 to 6.5). A high baseline NTx (> 67 units) indicated a 17.3 times higher risk of BMD loss if not treated with HRT. CONCLUSION: These data support the clinical utility of NTx to monitor the antiresorptive effect of HRT in recently postmenopausal women, and to predict changes in BMD in response to HRT.

Estrogen therapy and osteoporosis: principles & practice.

Postmenopausal osteoporosis is linked clearly to estrogen deprivation. Recent research has identified estrogen receptors in bone cells and in other organ systems that help to regulate bone remodeling and calcium homeostasis. Long-term use of estrogen in appropriate doses reduces the risk of hip fractures by 50% to 60% and the risk of vertebral deformation by 90%. This protective effect is maintained as long as estrogen is taken and adequate levels of biologically active estrogen are achieved. Thus, the type, dose, and route of administration of estrogen need to be individualized and the efficacy of treatment monitored by annual bone density testing and selective ultilization of biochemical bone markers. The ability of estrogen therapy to increase bone mass is enhanced by added androgens and progestin therapy, calcium supplementation, and exercise.

Urogenital aging: solutions in clinical practice.

Urogenital aging, the most prevalent consequence of the menopause, affects at least 50% of postmenopausal women. It can lead to a lower quality of life, sexual problems, pain at intercourse/micturition and incontinence, but is yet an undertreated condition. The ideal treatment should relieve the vaginal symptoms of estrogen deficiency, have a localized effect, be convenient and easy to apply, safe to the endometrium and be without the unpleasant discharge produced by vaginal creams and pessaries. Vagifem, a new vaginal tablet containing 25 microg 17beta-estradiol, may fulfill many of the criteria required of an agent for the effective and efficient management of urogenital atrophy.

Estrogen therapy in the management of problems associated with urogenital ageing: a simple diagnostic test and the effect of the route of hormone administration.

Estrogen deficient women are prone to problems such as vaginal dryness, dyspareunia and a predilection to recurrent urinary tract infections and urinary incontinence. A preliminary double-blinded study in 67 symptomatic postmenopausal women confirmed: (1) that atrophic vaginitis is associated with an increase in the lateral wall vaginal pH; (2) this is paralleled by similar changes in pH in the urethra; (3) locally applied vaginal conjugated estrogen cream normalizes the pH in the vagina and urethra. Thus, the testing of the vaginal pH serves both as a surrogate for evaluating urethral pH and as a monitor of compliance with treatment.

Contraceptive efficacy and safety of a monophasic oral contraceptive containing 150 micrograms desogestrel and 30 micrograms ethinyl estradiol: United States clinical experience using a "Sunday start" approach.

OBJECTIVE: To report on experience in the United States with a monophasic oral contraceptive (OC) containing 150 micrograms desogestrel and 30 micrograms ethinyl E2 (EE). The results of a multicenter evaluation of efficacy, cycle control, and safety over 6 months of exposure using a "Sunday start" regimen is evaluated. SETTING: Multicenter. DESIGN: Open noncomparative study. PARTICIPANTS: Study subjects were a mean age of 25 years, and the majority were educated, nonobese, white, nulliparous, and previously had used OCs. INTERVENTIONS: A total of 809 women were exposed to study medication for a total of 4,096 cycles (equivalent to 341.3 women-years of use). RESULTS: Efficacy was excellent. One user-failure pregnancy occurred (Pearl index 0.32); there were no method-failure pregnancies. Study medication was well tolerated; 6.6% of the subjects discontinued treatment because of drug-related adverse events. The study medication exhibited no adverse effects on blood pressure, body weight, or laboratory variables. Cycle control was evaluated in 697 subjects. In a total of 3,640 cycles, the incidences of intermenstrual bleeding, breakthrough bleeding, breakthrough spotting, and absence of withdrawal bleeding were 9.8%, 1.7%, 8.1%, and 1.4%, respectively, indicating appropriate cycle control. Patient acceptability was high; seven subjects (1%) discontinued the study because of menstrual irregularity (metrorrhagia). CONCLUSION: The results of this study, comparable to those demonstrated in a recent European multicenter study, add further documentation to the published data on the safety, efficacy, cycle control, and acceptability of this monophasic desogestrel-containing combined OC using a "Sunday start" approach.

Comparison of oral estrogens and estrogens plus androgen on bone mineral density, menopausal symptoms, and lipid-lipoprotein profiles in surgical menopause.

OBJECTIVE: To compare an oral estrogen-androgen combination with estrogens alone on bone, menopausal symptoms, and lipoprotein profiles in postmenopausal women. METHODS: Surgically menopausal women received oral esterified estrogens (1.25 mg), or esterified estrogens (1.25 mg) and methyltestosterone (2.5 mg) daily, for 2 years. Bone mineral density of the lumbar spine and hip, menopausal symptoms, lipoprotein profiles, and biochemical and hematologic indices were evaluated. RESULTS: Sixty-six patients were enrolled in the study. Both treatment regimens prevented bone loss at the spine and hip; combined estrogen-androgen therapy was associated with a significant increase in spinal bone mineral density compared with baseline (n = 24; mean score +/- standard error 3.4 +/- 1.2%, P < .01). In the estrogen group, high-density lipoprotein (HDL) cholesterol increased significantly and low-density lipoprotein cholesterol decreased significantly. Cholesterol, HDL cholesterol, and triglycerides decreased significantly in the estrogen-androgen group. Menopausal symptoms of somatic origin (hot flashes, vaginal dryness, and insomnia) were improved significantly by both treatments. Neither adverse hepatic effects nor significant safety or tolerance problems were reported in either group. CONCLUSION: Oral estrogen-androgen increased vertebral bone mineral density compared with pre-treatment values and relieved somatic symptoms. Safety indices, including lipoprotein levels, indicated that the combination was well tolerated over the 2 years of treatment.

The independent effects of exercise and estrogen on lipids and lipoproteins in postmenopausal women.

OBJECTIVE: To assess the effects of a moderate exercise program with and without oral estrogen replacement on levels of lipids and lipoproteins in postmenopausal women. METHODS: One hundred one postmenopausal women were randomized into four groups: control or sedentary (N = 20), exercise alone (N = 25), estrogen replacement using 0.625 mg conjugated equine estrogen (N = 28), and exercise supplemented with conjugated equine estrogen (N = 28). The exercise groups were placed on a moderate exercise program. Following baseline testing, each group returned at 3 and 6 months for cardiorespiratory fitness testing and serum lipid and lipoprotein profiles. RESULTS: We found a significant decrease in systolic blood pressure (P < .05) in all treatment groups. The maximum oxygen uptake increased by 9.0 and 7.8% in the exercise and conjugated equine estrogen/exercise groups, respectively, compared to the other groups (P < .05). These responses were seen at both 3 and 6 months. Total exercise time (time spent on the treadmill until exhaustion during testing) significantly increased in the exercise group by 21% (P < .01). Exercise alone was associated with significant decreases in total cholesterol (5.2%, P < .05), triglycerides (2%, P < .05), and low-density lipoprotein (LDL) cholesterol (10%, P < .01), and a significant increase in the high-density lipoprotein (HDL) cholesterol-LDL ratio (17.2%, P < .01). Significant changes were noted in these values, as well as increases in HDL cholesterol (16 and 14.8%; P < .01) and apolipoprotein A1 (25.6 and 26.5%; P < .001) in the conjugated equine estrogen and conjugated equine estrogen/exercise groups, respectively. However, there were no differences in the changes observed in the conjugated equine estrogen groups with versus without exercise. No direct correlation was seen between measures of exercise performance and the changes seen in lipids and lipoproteins. CONCLUSIONS: Estrogen therapy alone had the greatest beneficial effect on lipids and lipoproteins. Exercise alone resulted in a significant reduction in cholesterol, triglycerides, and LDL cholesterol, and an increase in the HDL-LDL ratio. However, combined conjugated equine estrogen and exercise did not demonstrate an added improvement in lipid metabolism. Physical fitness levels increased in the exercise groups, but not in the control group or the estrogen-alone treated women.

Effects of aerobic training on bone mineral density of postmenopausal women.

A total of 76 women were enrolled and 55 naturally postmenopausal women completed a 12 month study investigating the effects of aerobic training plus calcium supplementation on lumbar (L2-4) bone mineral density (BMD) and forearm BMD. Training was conducted on treadmills at 70-85% of maximal heart rate for 30 or 45 minutes, three times per week for 12 months. Lumbar BMD was measured with dual-photon absorptiometry and forearm BMD with single-photon absorptiometry. Groups were similar with respect to age, weight, months since menopause, height, maximal oxygen uptake (VO2max), and lumbar and forearm BMD upon entering the study. Following training, percentage changes in VO2max were significantly different between the control and exercise groups but not between exercise groups. ANOVA evaluating lumbar BMD revealed a nonsignificant interaction effect and no significant changes (p > 0.05) between groups or times. The control (N = 19), 30 minute (N = 20), and 45 minute (N = 16) groups percentage lumbar BMD changes (X +/- SD) over 12 months were -0.61 +/- 3.40, -0.48 +/- 3.63, and 0.81 +/- 4.53%, respectively. The 95% confidence limits for percentage changes in lumbar BMD for the control, 30 minute, and 45 minute groups were -2.25 to 1.02, -2.18 to 1.22, and -1.16 to 3.22%, respectively. Forearm BMD changes were also not significant. Improvement in lumbar BMD was weakly but positively correlated with improvements in VO2max, r = 0.28, p < 0.05. Women < or = 6 years of the onset of menopause had an accelerated lumbar BMD loss compared to subjects who were > 6 years postmenopausal, and this subset's BMD changes were examined.(ABSTRACT TRUNCATED AT 250 WORDS)

Osteoporosis: screening, prevention, and management.

OBJECTIVE: To present clinical recommendations for osteoporosis prevention that include new support for routine bone mass screening of asymptomatic perimenopausal high-risk women. Technological advances make it conceivable that osteoporosis, a metabolic bone disorder rather than a true disease, can be prevented on a wide scale and eventually eliminated. Effective prevention requires that advanced screening procedures be easily accessible and reimbursable as a wise healthcare investment. STUDY SELECTION: This article reviews research bearing on clinical management of women potentially at risk for osteopenia and osteoporosis. Background includes the pathogenesis of osteoporosis and known risk factors such as heredity, life-style, gynecological history, eating disorders, endocrinopathies, and scoliosis. Studies of bone mass measurement favor dual-energy roentgenographic absorptiometry as the bone densitometry method of choice for screening women at risk and for use with roentgenograms in evaluating bone health. The balance between bone formation and resorption can be assessed by a number of biochemical markers, which are reviewed. Other factors known to affect bone mass are discussed. CONCLUSIONS: Primary care physicians, especially gynecologists, can play a pivotal role by [1] identifying women with higher risks for osteoporosis at earlier ages; [2] stressing the importance of developing maximal bone mass before menopause; and [3] developing individualized patient prescriptions for bone mass determinants under personal control: exercise, nutrition (e.g., calcium and vitamin D), life-style, and hormone replacement therapy.