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Estradiol Absorption From Vaginal Tablets in Postmenopausal Women

Notelovitz, M. MD, PhD; Funk, S. MD; Nanavati, N. MS; Mazzeo, M. MS

ORIGINAL RESEARCH
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OBJECTIVE To evaluate absorption of estradiol (E2) and compare two low doses of 17 β-E2 (25 μg and 10 μg) in postmenopausal women with atrophic vaginitis.

METHODS In a double-masked, randomized, parallel-group study, 58 postmenopausal women were treated with 25 μg or 10 μg of 17 β-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-μg (563 pg · hour/mL, 49 and 23 pg/mL) than in the 10-μg (264 pg · hour/mL, 22 and 11 pg/mL) group. Seventy-four percent in the 25-μg and 96% in the 10-μg 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 μg had mean FSH levels below 35 mIU/mL.

CONCLUSION Treatment with 25 or 10 μg of 17 β-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.

Treating atrophic vaginitis with low-dose 17 b-estradiol tablets results in consistent, low absorption of estradiol without accumulation.

Women's Medical and Diagnostic Center and the Climacteric Clinic Inc, Gainesville, Florida; Hill Top Research, Inc, Atlanta, Georgia; and Novo Nordisk Pharmaceuticals, Inc, Princeton, New Jersey.

Address reprint requests to: M. Notelovitz, MD, PhD, Adult Women's Medicine, 2801 NW 58th Boulevard Gainesville, FL 32605; E-mail: mnotelo@aol.com.

Financial Disclosure

Supported by Novo Nordisk A/S of Denmark. M. Notelovitz is a paid consultant to this company. M. Mazzeo is an employee of the company and owns stock in it. Novo Nordisk A/S manufactures hormone replacement products.

Received July 11, 2001. Received in revised form January 22, 2001. Accepted March 1, 2001.

Over half of postmenopausal women will have urogenital discomfort associated with estrogen deficiency. 1,2 A previous study 2 found that although many women use oral hormone replacement therapy (HRT), urogenital symptoms persist. Many women can get additional benefits from local therapy.

Vaginal administration of low-dose estradiol (E2) tablets offers safe and convenient local relief of vaginal symptoms. 1,3,4 Vaginal estrogen is often more effective for relieving urogenital symptoms than conventional systemic estrogen therapy because hepatic metabolism is avoided and vaginal tissues have increased response to locally applied estrogen. Those characteristics make it possible to use significantly lower doses of estrogen with local therapy compared with oral therapy.

Studies have shown that vaginal estrogen preparations can result in rapid and efficient absorption of E2 into systemic circulation. 5,6 However, low-dose preparations that contain 10 and 25 μg of E2 effectively relieve symptoms of atrophic vaginitis without unwanted systemic side effects. 3,6 A low-dose (25 μg) 17 β-E2 vaginal tablet (Vagifem, Novo Nordisk, Baegsvard, Denmark) has been developed to treat estrogen-deficient atrophic vaginitis. Those tablets contain a film-coated hydrophilic cellulose matrix that adheres well to the vaginal epithelium and hydrates slowly to provide a controlled release of E2. They are designed to provide estrogenization of the vaginal epithelium while preventing significant increases in serum estrogen concentrations.

In this study, the vaginal absorption of E2 was evaluated, and two low doses of 17 β-E2 (25 μg and 10 μg) were compared in postmenopausal women with atrophic vaginitis.

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MATERIALS AND METHODS

This single-center, randomized, double-masked, parallel-group study was conducted in Atlanta, GA. The study was approved by the appropriate institutional review board, and written informed consent was obtained from each subject. The study was conducted in compliance with the Declaration of Helsinki of 1975, revised in 1983.

We enrolled generally healthy, postmenopausal women (with or without uteri), aged 45 years or older. Subjects had no more than 5% superficial cells, assessed by vaginal cytology, and serum E2 concentrations no greater than 20 pg/mL. Women with uteri had endometrial thicknesses no greater than 4 mm, measured by pelvic ultrasound. We excluded women with known or suspected histories of breast cancer or other hormone-dependent tumors, acute thrombophlebitis or thromboembolic disorders associated with previous estrogen use, or vaginal infection that required further treatment (at baseline) and those with genital bleeding of unknown etiologies (within 12 months before screening). Subjects were not to have used any type of vaginal, oral, or vulvar preparations within 7 days of screening (except for nutritional supplements); exogenous corticosteroid or sex hormones within 8 weeks before baseline; investigational new drugs within the past 30 days; or diethylstilbestrol.

After screening visits, subjects received no study treatment during the 4-week run-in period before the baseline visit. At that visit, they were randomized to receive vaginal tablets that contained either 25 or 10 μg of 17 β-E2 on a 1:1 basis using a computer-generated scheme. The vaginal tablets were identical and labeled only with a code. Codes were kept in sealed envelopes to be opened in case of emergency, which did not happen in this study. Women inserted one tablet intravaginally, once daily for 2 weeks and then twice per week (Sunday and Thursday) for the remaining 10 weeks. They were instructed to use their medication at a consistent time each day, preferably in the morning. After baseline visits, participants returned to the clinic at weeks 1, 2, 4, 8, and 12 for measurements of serum E2 and FSH and vaginal cytology.

At each visit, a vaginal cytology specimen was collected and women then inserted the tablets. Blood samples were drawn 30 minutes before insertion, and at 1, 2, 4, 5, 6, 7, 8, 10, 12, and 24 hours after insertion for measurement of serum E2 concentration by radioimmunoassay (Nichols Institute, San Juan Capistrano, CA). Blood samples collected at 30 minutes before insertion, and at 6, 12, and 24 hours after insertion also were used to measure FSH concentrations by chemiluminescense assay (Nichols Institute, San Juan Capistrano, CA).

The maturation value of vaginal epithelial cells was calculated from percentages of parabasal, intermediate, and superficial cells according to the following equation:

The area under the concentration-time curve from 30 minutes before tablet insertion to 24 hours after insertion, maximal concentration, and time to maximal concentration were measured for serum concentrations of E2. Data for area under the curve and maximal concentration were converted to logarithmic scales, and changes from first dose (at baseline visit) in the logarithmic values were estimated. Differences between treatment groups in the degree of absorption of E2 were determined using 95% confidence intervals and from two sample t tests based on observed mean values of logarithms of area under the curve and maximal concentration. Mean concentrations were defined as average concentrations at 30 minutes before tablet insertion and 6, 12, and 24 hours after insertion. Baseline concentrations for E2 and FSH were defined as values observed at 30 minutes before tablet insertion at baseline visits.

This manuscript presents data for the eligible population, which was defined as those women 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.

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RESULTS

A total of 58 women were treated with vaginal tablets that contained either 25 μg of 17 β-E2 (n = 28) or 10 μg of 17 β-E2 (n = 30). Ten women discontinued the study prematurely: six in the 25-μg 17 β-E2 group (one because of an adverse event, two because of noncompliance with the protocol, two from the inability of site personnel to collect venous samples, and one from an ongoing vaginal infection), and four in the 10-μg 17 β-E2 group (one from noncompliance with the protocol, one from the inability of site personnel to obtain a venous sample, one from relocation, and one because of elective surgery). The eligible population comprised 42 women, 19 who received 25 μg of 17 β-E2, and 23 who received 10 μg of 17 β-E2. Demographic and baseline characteristics for the eligible population are presented in Table 1. Patient characteristics were similar between groups, with the exception of percentage of parabasal cells at baseline, which was significantly lower for patients in the 25-μg group compared with those in the 10-μg 17 β-E2 group (P = .027, t test).

Table 1

Table 1

The 24-hour concentration absorption patterns for serum E2 at weeks 0 and 12 are presented in Figures 1 and 2, respectively, and the associated pharmacokinetic characteristics are presented in Table 2. At weeks 0 and 12, serum E2 absorption patterns were similar within each group. The mean area under the curve and maximal concentration from the serum E2 concentration profile were significantly higher for women who received 25 μg than 10 μg. However, this result should be interpreted with caution because the baseline comparability between the two treated groups could not be assessed due to the lack of true baseline profile.

Notelovitz

Notelovitz

Estradiol Absorption

Estradiol Absorption

Table 2

Table 2

A comparison between the areas under the curve for serum E2 at weeks 0 and 12 is presented in Figure 3. Most women in each group had areas under the curve below 500 pg · hour/mL at both points (14 [74%] and 22 [96%] in the 25- and 10-μg groups, respectively). A comparison between area under the curve for serum E2 and mean FSH concentration at week 12 is presented in Figure 4. At week 12, most women in each treatment group had mean FSH concentrations in the normal postmenopausal range (at least 35 mIU/mL); three in the 25-μg group had mean FSH concentrations below 35 mIU/mL.

Notelovitz

Notelovitz

Notelovitz

Notelovitz

The mean maturation value and mean change from baseline in maturation value are presented in Table 3. In each treatment group, subjects experienced significant increases in maturation value over baseline values (P ≤ .001 at weeks 1 and 2, and P ≤ .01 at week 12; two-tailed, paired t test). At all points, mean maturation values and mean changes from baseline in maturation value were comparable between groups. A comparison between the area under the curve for serum E2 and the maturation value at week 12 is presented in Figure 5. Most women in each treatment group (13 [68%] and 14 [64%] in the 25- and 10-μg groups, respectively) showed increased maturation values from corresponding baseline values (53.4% and 51.0% in the 25-and 10-μg groups, respectively).

Notelovitz

Notelovitz

Table 3

Table 3

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DISCUSSION

Atrophic vaginitis and other forms of urogenital discomfort caused by estrogen deficiency will affect over half of postmenopausal women. 1,2 These conditions commonly were treated before with systemic HRT and locally applied estrogen creams. Low-dose therapies that deliver estrogen directly to the vaginal tissue have provided recent alternative therapeutic options. Optimum intra-vaginal therapy will provide consistent estrogen absorption with adequate vaginal symptom relief without systemic absorption and associated side effects. 3,6

We examined systemic absorption of E2 in women treated with either 25- or 10-μg 17 β-E2 vaginal tablets for 12 weeks. Most in each group (74% in the 25-μg and 96% in the 10-μg group) had low systemic absorption of E2 at the beginning and end of 12-weeks treatment, indicated by areas under the serum E2 concentration curve below 500 pg · hour/mL at each time point. Among six remaining subjects, four who had higher E2 absorption at week 12 also had areas under the curve greater than 500 pg · hour/mL at week 0, suggesting they were characteristically high E2 absorbers. It is likely that those women would have greater absorption of E2 from any systemic estrogen replacement.

The 24-hour serum E2 absorption patterns at weeks 0 and 12 were similar for each group, again indicating that women overall had consistent E2 absorption patterns at the beginning and end of treatment. The average E2 concentrations at each time point were within the normal post-menopausal range (normal postmenopausal range for E2 concentration up to 40 pg/mL). In contrast, other studies reported marked decreases in E2 absorption with systemic estrogen replacement. Those decreases are often attributed to saturation of E2 receptors during vaginal maturation. 3 Although vaginal administration of estrogen is often used to treat atrophic vaginitis, the exact mechanism for E2 absorption through the vagina has not been clearly defined. The promising results from this study showed consistent E2 absorption over 12 weeks of treatment. However, only long-term therapy will maintain the health of the vaginal tissue, and further extended studies are needed.

The biologic efficacy of absorbed E2 might vary among women. Although they may be relatively high E2 absorbers, the biologic potency might be reduced (eg, by binding to serum hormone-binding globulin), and the women might not have marked FSH suppression. In this study, after 12 weeks of treatment with 25 or 10 μg of 17 β-E2, FSH concentrations were rarely suppressed to premenopausal levels, suggesting that the increase in serum E2 concentration was not associated with clinically significant systemic E2 potency. The E2 and FSH concentrations in this study were consistent with results from an independent study in which women received either 25 μg of 17 β-E2 tablets or 1.25 mg of conjugated equine estrogen cream (Premarin, Wyeth-Ayerst, Philadelphia, PA). Over that 6-month study, significantly fewer women who received 25-μg tablets had E2 or FSH concentrations outside the normal postmenopausal ranges compared with those who received the vaginal cream (normal postmenopausal ranges in the 6-month study: serum E2 concentration, up to 49 pg/mL; FSH concentration, up to 35 mIU/L). 7 In the same study, the likelihood of endometrial hyperplasia was reduced in women treated with 25-μg 17 β-E2 tablets compared with those treated with vaginal cream.

Maturation value measures the effect of absorbed estrogen and provides a quantitative assessment of the condition of the vaginal epithelium. Participants in each treatment group showed significant improvement (P ≤ .01) in the condition of the vaginal epithelium, indicated by increases in maturation value. After 12 weeks of treatment, most subjects (over 60%) in each treatment group had increased maturation values. Although the 25- and 10-μg 17 β-E2 dose levels had positive effects on atrophic vaginal epitheliums while maintaining low serum concentrations of E2, a relationship between increased maturation values and E2 blood levels could not be discerned. Thus, although E2 absorption is important, it is not necessarily indicative of the clinical effect of estrogen therapy. The improvement in vaginal health might be from direct perfusion or lymphatic absorption of the local E2 through the vaginal epithelium. In this study, vaginal maturity was measured exclusively with maturation value. The vaginal response is likely caused by enhanced glycogenization and acidification of the vagina, so monitoring the vaginal pH would provide another useful measure of vaginal health. 8,9

Although vaginal maturation with low concentrations of circulating E2 is a primary treatment goal of local vaginal HRT, other independent studies have also associated vaginally administered HRT with maturation of the urethral epithelium. 3 Reduced risks of osteoporosis in postmenopausal women also have been observed. 10–12 Those benefits likely rely on the concentration of circulating E2 added to the endogenous production of E2 in bone, which is especially true in older, naturally postmenopausal women. 10 The average serum E2 concentrations were higher for women who received 25 μg of 17 β-E2 than those who received 10 μg, so it is possible that women who receive the higher dose might derive additional benefits in increased bone strength while maintaining serum E2 concentrations within a physiologic (perimenopausal) range.

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© 2002 The American College of Obstetricians and Gynecologists