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Abstract

A novel micellar, nanoparticle emulsion containing 17β-estradiol is currently available as a daily topical treatment for moderate-to-severe vasomotor symptoms associated with menopause. Applied daily to the lower extremities, the emulsion delivers 0.05 mg estradiol systemically and provides an 85% reduction in hot flash frequency versus baseline by 12 weeks of therapy. When specifically surveyed, most patients felt that this cosmetic-like delivery system was convenient and preferable to transdermal patches. Local skin reactions, all mild, were seen in 4%, and there was a low incidence of side effects that included breast pain, endometrial thickening and headache. Contraindications include those common to all estrogen-containing therapies. This formulation provides patients with a cosmetic-like treatment option that is effective and safe, delivers stable systemic estradiol levels, and may promote overall treatment compliance.

Keywords

estradiol topical emulsion hormone replacement micellar nanoparticle estradiol emulsion vasomotor symptoms

Estrogen is the most effective treatment available for the relief of menopausal vasomotor symptoms (hot flashes and night sweats) and vaginal atrophy with its associated symptoms of dryness, itching and dyspareunia [1]. At one time, it was thought that hormone therapy (HT) (either estrogen, progesterone or both) could also provide long-term protection for women against cardiovascular disease, osteoporosis and cognitive decline, while improving quality of life. Beginning in 2002, with the release of the first results of the Women's Health Initiative (WHI), many of these touted benefits of HT were called into question [2 –4]. The WHI reports received considerable media attention and led to a decline in prescriptions written by clinicians and a patient population reluctant to take HT [5,6].

Although the WHI challenged conventional wisdom regarding the benefits of long-term HT for disease prevention, it was not intended to study the effectiveness of HT in relieving menopausal symptoms. Due to fear of hormone-related sequelae, however, many women subsequently discontinued HT use. Today, the primary indication for HT remains the treatment of menopausal symptoms. In response to WHI, the American Society of Reproductive Medicine, the American College of Obstetrics and Gynecology, and the North American Menopause Society issued position statements endorsing use of the lowest effective dose of HT for the relief of hot flashes for the shortest possible duration consistent with the therapeutic goal specific to the individual patient [1,7,8].

Estradiol, the most potent naturally occurring human estrogen, may be administered alone in women who have undergone a hysterectomy or with a progestin in women with an intact uterus [9]. Estradiol is available in oral, transdermal, injectable and local formulations. One of the newest transdermal therapies, estradiol topical emulsion ([ETE]; Estrasorb®; Esprit Pharma, Inc., NJ, USA), was recently approved by the US FDA for the treatment of moderate-to-severe hot flashes [10]. The novel delivery system of ETE, known as a micellar nanoparticle estradiol emulsion, is created by mixing soy bean oil, water, surfactant, alcohol and estradiol by a proprietary process; the resulting emulsion contains 2.5 mg estradiol/g of lotion [11]. Having the feel of a cosmetic lotion, ETE lacks the skin-irritating side effects often seen with transdermal patches. This formulation may be more appealing to postmenopausal women who are reticent to take a tablet, prefer not to apply a transdermal patch, or dislike the drying effects of alcohol-based delivery systems.

Currently available estrogen-containing therapies

Systemic estrogens

The most widely used estrogen-containing therapies in the USA are conjugated equine estrogens (CEE) and estradiol. These have been prescribed most frequently as oral formulations. Both CEE and estradiol are more effective than placebo in relieving menopausal hot flashes, and it does not appear that differences in efficacy of these agents are significant across the range of doses commonly used [12,13]. Owing to the endometrial effects of unopposed estrogens, the addition of a progestin is recommended when a woman who has not had a hysterectomy receives any systemic estrogen therapy (ET).

Nonoral estrogen-containing formulations, delivering estradiol systemically, are being prescribed with increasing frequency. Nonoral delivery systems vary and include transdermal patches, vaginal rings, a gel and an emulsion (Estrasorb). They avoid first-pass metabolism in the liver, and with subsequent lower concentrations of estrogen in the portal vein and liver, yield smaller alterations in hepatic-derived proteins such as C-reactive protein, serum amyloid A, and serum lipids (low-density lipoprotein cholesterol and triglycerides) [14,15].

Transdermal estradiol patches include Vivelle® and Vivelle-dot® (Novogyne Pharmaceuticals, USA), Alora® (Watson Pharmaceuticals, Inc., CA, USA), Estraderm® (Novartis Pharmaceuticals Corp., NJ, USA), Climara® (Berlex, Inc., NJ, USA) and others [16 –20]. These patches are applied once or twice weekly depending on the specific product, and several are available in multiple dosage strengths. Approved indications also vary among the patches, but may include the treatment of vasomotor symptoms, urogenital atrophy, hypoestrogenism and osteoporosis prevention.

An estradiol-containing vaginal ring (Femring™, Warner Chilcott Co., NJ, USA) is approved for the treatment of vasomotor and urogenital symptoms [21]. This silastic ring is available in two strengths and delivers 0.05- or 0.10-mg estradiol/day systemically.

In 2004, estradiol gel (EstroGel®, Solvay Pharmaceuticals, Inc., GA, USA) was approved by the FDA [22]. This hydroalcoholic gel is available in a 1.25- g dose (containing 0.75 mg estradiol) and has been shown to be effective in reducing both the frequency and severity of vasomotor symptoms associated with menopause.

Local estrogens

Some delivery systems are designed to supply doses of estrogen only for local treatment, rather than systemic treatment, of estrogen deficiency-related symptoms. These local or topical vaginal estrogens are prescribed only for the treatment of urogenital symptoms associated with atrophy of the vagina and lower urinary tract. Progestins are not needed for endometrial protection with local vaginal therapy. Estring™ (Pharmacia [now part of Pfizer, Inc., NJ, USA]), a vaginal ring, is one such agent [23]. Estrace® cream (Warner Chilcott) [24], generic estradiol-containing creams and the CEE-containing Premarin® cream (Wyeth, Inc., NJ, USA) [25] are available for intravaginal use. Vagifem™ (Novo Nordisk Pharmaceuticals Ltd, Crawley, UK) is a vaginal tablet approved only for the treatment of vulvar and vaginal atrophy [26].

Nonhormonal therapies

Several nonhormonal therapies used off-label for the treatment of menopausal symptoms include: antihypertensives, such as clonidine; anticonvulsants, such as gabapentin; and selective serotonin-reuptake inhibitors, including paroxetine and fluoxetine, and the selective serotonin/norepinephrine-reuptake inhibitor venlafaxine [27 –31]. These agents may be suitable for women who will not take HT or are not candidates for HT [8,27].

Estradiol topical emulsion

The topical ETE formulation is approved for the treatment of moderate-to-severe vasomotor symptoms associated with menopause. It is applied once/day [10]. One dose consists of two packets, each containing 1.74 g of product; the contents are applied to the thigh and calf of both legs. This dose delivers 2.5 mg estradiol/g to the skin; less than 1% is absorbed into the systemic circulation (0.05 mg) and the remainder is distributed on the skin surface or in the subcutaneous/intracutaneous reservoir ( Figure 1 ).

Figure 1.

Cutaneous absorption of estradiol topical emulsion (Estrasorb®) and its entry into the systemic circulation.

Chemistry

The chemical name is 17β-estra-1,3,5(10)-triene-3,17-diol, hemihydrate. This topical ETE is delivered using new technology known as the micellar nanoparticle estradiol emulsion. This lotion-like emulsion is a mixture of estradiol, soy bean oil, polysorbate 80 (a surfactant), water, and ethanol [10]. The micelles in the emulsion are lipid structures averaging 560 nm in diameter that encapsulate the estradiol and deliver it into the stratum corneum, epidermis and eventually into the deeper layers of the skin until it reaches the bloodstream, with subsequent elevation of plasma concentrations of estradiol [32].

Pharmacodynamics

In a Phase II multiple-dose study (n = 125) of 4 weeks' duration, changes in the mean (± standard error of the mean [SEM]) trough serum concentrations were highest in the 3.45 g treatment group (40 ± 8.6 pg/ml), followed by the 2.3 g treatment group (34 ± 6.2 pg/ml) and the 1.15 g treatment group (23 ± 5.7 pg/ml) [32]. Mean (±SEM) trough serum estradiol levels at end point were 56 ± 8.0 pg/ml, 43 ± 7.9 pg/ml, and 30 ± 6.2 pg/ml, respectively, in the 3.45, 2.30 and 1.15 g treatment groups. There was good correlation between trough serum levels and the number of daily hot flashes.

Pharmacokinetics & metabolism

Pharmacokinetics

The systemic absorption of ETE is 0.05 mg of estradiol/day [10]. When ETE was applied daily for 8 days in eight symptomatic women, it was found that the absolute bioavailability was 0.66%, the terminal exponential half-life was approximately 2.4 days, and steady state was reached by day 8 in 80% of subjects [32]. The accumulation index was approximately 4, indicating sustained-release delivery. As discussed in the pharmacodynamics section, the Phase II multiple-dose study demonstrated that the mean change from baseline in serum estradiol concentrations increased in a dose-dependent manner [10]. Given that the nanoparticle delivery system allows estradiol to diffuse gradually into the bloodstream, no major fluctuations in serum estradiol levels were observed, creating stable systemic levels. In a 12-week, Phase III study that compared the daily 3.45-g dose of ETE with placebo, mean estradiol and estrone concentrations in the treatment group were increased at week 2 and maintained for the duration of the study ( Figure 2 ) [33]. By week 12, serum estradiol had increased from 9 pg/ml at baseline to 63 pg/ml.

Figure 2.

Mean serum levels of estradiol (A) and estrone (B) in patients treated with estradiol topical emulsion or placebo.

Residual estradiol can be found on the skin after application of ETE [32]. When assessed in 12 women, the amount remaining on the skin following a single dose ranged from 220 to 803 μg estradiol at 2 h post application, and from 70 to 582 μg at 8 h post application. Thus, a second study assessed whether residual estradiol could be transferred to male partners via skin-to-skin contact with female partners (n = 14 couples). On two consecutive days, male partners attempted to transfer estradiol by vigorously rubbing their forearms against their female partners' thighs for 2 min at 2 and 8 h after application of ETE to the female partner. Estradiol levels (as measured by the area under the plasma–time curve of estradiol) increased in the male partners by up to 25% compared with baseline; however, levels were still within the normal male range for all of the male subjects (time-averaged levels [C_avg]: 21.0 ± 4.4 pg/ml compared with pre-exposure levels, C_avg: 17.0 ± 4.3 pg/ml, upper limit of normal for men, 50 pg/ml) [10].

Application of sunscreen 10 min prior to the application of ETE increased serum estradiol levels by 35%, while sunscreen application 25 min after the application of ETE increased exposure 15% [10]. Therefore, while neither of these increases were large, it is recommended that ETE not be applied within 30 min of sunscreen [10].

Metabolism

There are important metabolic differences between transdermal and oral delivery systems. Unlike transdermal formulations, oral estrogens are subject to extensive first-pass effects in the liver, altering hepatic protein synthesis and metabolism [34,35]. In comparison with transdermal formulations, large doses of oral estradiol must be taken in order to achieve therapeutic levels and oral formulations can produce fluctuating estradiol and estrone levels. Transdermal estrogens are introduced directly to the systemic circulation, provide a more physiological estradiol:estrone ratio, result in steadier serum estradiol levels and may result in a lower risk of deep vein thrombosis [36]. As transdermal estradiol avoids first-pass effects in the liver, it minimally affects hepatic protein synthesis and metabolism while delivering appropriate levels of estradiol at a constant rate.

Clinical efficacy

Phase II study

A double-blind, placebo-controlled study assessed the efficacy and safety of three doses of ETE (1.15, 2.30 or 3.45 g of emulsion, containing 2.5 mg of estradiol/g) in 125 post-menopausal women treated for 28 treatment days. The number and severity of hot flashes during a 1-week placebo run-in period prior to treatment and during the 28 treatment days were recorded in patient diaries. At week 4, 17% of subjects in the 2.30 g ETE group and 22% of subjects in the 1.15-g ETE group reported no moderate to severe hot flashes compared with 9% of subjects treated with placebo; these response rates were greatly exceeded by the 3.45-g ETE treatment group, in which 45% of subjects reported no moderate-to-severe hot flashes [32]. Therefore, the 3.45-g dose was used in the pivotal Phase III study.

Interestingly, a subsequent marketing analysis conducted among these women found that 72% who had previously used a transdermal patch indicated that they would switch to ETE; and 91% reported that they liked the way their skin felt after ETE application [32].

Phase III study

A randomized, double-blind, placebo-controlled clinical trial was conducted at 21 centers across the USA and enrolled 200 postmenopausal women for 12 weeks of treatment [33]. The primary efficacy parameter was the change from baseline in the average daily count of moderate-to-severe hot flashes at weeks 4 and 12. By week 3, significant differences from placebo were observed with the daily 3.45 g ETE treatment (p = 0.003) and this effect was sustained from weeks 4–12 (Figure 3). The maximal reduction (85%) in frequency of hot flashes in patients receiving ETE was observed at week 12 (−11.1 ± 6.8 hot flashes/day compared with −7.2 ± 5.4 hot flashes/day for placebo; p < 0.001). By 12 weeks, 68% of women in the ETE group reported 90% or greater reduction in vasomotor symptoms versus only 31% in the placebo group.

Figure 3.

Mean change from baseline in average daily count of moderate-to-severe hot flashes in patients receiving estradiol topical emulsion or placebo emulsion.

Safety & tolerability

Adverse events associated with ETE use in clinical trials are typical for estrogen-containing compounds as a class; the emulsion has been found to be safe and well tolerated. A summary of adverse events for the combined clinical trials to date is presented in Table 1. The most commonly reported adverse events included infection, endometrial disorders, breast pain, application-site reaction, pruritus, vaginal bleeding and moniliasis. In the Phase I, II, and III studies there were three serious adverse events recorded in the ETE groups. These included depression requiring hospitalization, lumbar pain requiring a laminectomy and cervical pain with subsequent cervical diskectomy. No deaths occurred in any of the studies.

Table 1.

Number (%) of treatment-emergent adverse events.

Adverse event	Placebo (n = 134)	Estradiol topical emulsion (n = 210)
≥1 Treatment-emergent adverse event	82 (61)	121 (60)
Abdominal pain	6 (4)	8 (4)
Headache	17 (13)	15 (7)
Infection	10 (7)	19 (9)
Dyspepsia	3 (2)	2 (<1)
Flatulence	1 (<1)	6 (3)
Nausea	4 (3)	3 (1)
Peripheral edema	1 (<1)	4 (2)
Weight gain	0	4 (2)
Depression	3 (2)	1 (<1)
Dizziness	3 (2)	1 (<1)
Acne	0	3 (1)
Application-site reaction	4 (3)	8 (4)
Pruritus	0	8 (4)
Breast pain	4 (3)	16 (8)
Endometrial disorders	11 (8)	21 (10)
Urinary tract infection	1 (<1)	4 (2)
Enlarged uterine leiomyoma	3 (2)	2 (<1)
Vaginal bleeding	0	7 (3)
Vaginal moniliasis	0	6 (3)

Regulatory affairs

In October 2003, ETE was approved by the FDA for the treatment of moderate-to-severe vasomotor symptoms. It was launched in the USA in April 2004. A Phase IV study is planned to assess a lower dose of ETE for treatment than that which currently is approved.

Conclusion

The micellar nanoparticle emulsion of ETE, a unique topical alternative for the delivery of estradiol, is approved for the treatment of menopausal symptoms. This treatment option offers an 85% reduction in hot flash symptoms with minimal side effects. In all the studies combined, the percentage of subjects receiving ETE who withdrew was 1% (3 of 201 subjects), whereas the withdrawal rate was 3% (4 of 134 subjects) in the placebo group, thus demonstrating the tolerability of ETE. Furthermore, a marketing analysis found that 72% of women who previously had used a patch delivery system for ET said they would switch to ETE, and 91% said they liked the way their skin felt after its application [32]. This novel cosmetic-like delivery system may appeal to women as a preferable alternative to both tablets and transdermal patches.

Future perspective

The ideal HT is one that provides symptom relief, has a benign side-effect profile and promotes patient compliance. While the WHI findings contradicted what many observational studies had found with respect to primary and secondary preventive effects (such as for cardiovascular disease), the value of ET and HT in general should not be entirely discounted [37,38]. There still are many unanswered questions regarding HT, including:

What are the appropriate formulations of HT?

How do different delivery systems affect drug efficacy?

How should clinical efficacy be measured?

What are the most appropriate populations to study?

What is the best time to initiate therapy?

How do different progestins affect metabolism and clinical outcomes?

Future research should further characterize the different types and routes of delivery of estrogens, expand our understanding of their effects on physiology and metabolism and evaluate the side-effect profile of various formulations. Estrone makes up the major portion of estrogens in CEE, the agent used in WHI. Estradiol, however, may be a more appropriate choice for ET. Estradiol both orally and transdermally has a much smaller impact on hepatic enzymatic activity, and this may result in a favorable metabolic profile, especially in transdermal formulations. Unfortunately, there are no large-scale studies comparing CEE with 17β-estradiol and, in light of the WHI, the CEE findings have been extended to all estrogen-containing compounds, especially in terms of the benefit–risk profile.

Although WHI caused an abrupt decrease in the usage of HT, patients and clinicians are cautiously rethinking its use for a number of reasons. First, estrogen is truly the most efficacious way to treat menopausal symptoms. Studies are needed to ascertain if different estrogen preparations offer superior outcomes in terms of efficacy and safety. Second, recent data indicate that the duration of usage is related to the risk of major adverse events. Specifically, the Nurses Study found that an increased risk of breast cancer occurred only after 15 years of use [39]. Additional data suggest that the timing of HT initiation in relation to the onset of menopause or a woman's age may influence coronary outcomes. Grodstein and colleagues found a 30% reduction in risk of coronary heart disease for women who began HT (estrogen alone or combined HT) near menopause compared with postmenopausal women who never used hormones [40]. Furthermore, the study suggested that the apparent benefits of hormones decreased when therapy was initiated long after the onset of menopause or at older ages. There appears to be a decreased risk of coronary heart disease for women who began ET near menopause [41]. Use of an appropriate ET formulation initiated at an appropriate time may be an important variable in calculating risks and benefits; two studies now underway are investigating this issue. The first study is Early versus Late Intervention Trial with Estradiol (ELITE), which will investigate whether oral 17β-estradiol will reduce the progression of early atherosclerosis if initiated soon after menopause when the vascular endothelium is thought to be relatively healthy versus later when the endothelium may have lost its responsiveness to estrogen [101]. The second study, Kronos Early Estrogen Prevention Study (KEEPS), will also use carotid ultrasonography and will assess atherosclerotic progression in women aged 42–58 years treated with 0.45 mg/day of oral CEE or 50 μg/day of transdermal estradiol via skin patch versus placebo [102].

In conclusion, HT is even more complex than once was thought. Therefore, each menopausal woman, in consultation with her physician, must evaluate the benefits and risks of HT. Transdermal estradiol appears to be a safe and effective intervention for the short-term treatment of menopause-related vasomotor symptoms. For many women, the ETE delivery system may be an appealing choice.

Information resources

American College of Obstetricians and Gynecologists Women's Health Care Physicians: Vasomotor Symptoms. Obstet. Gynecol. 104(Suppl. 4), S106–S117 (2004).

Estrasorb® website

www.estrasorb.com

Executive summary

Dosing & administration

Estradiol topical emulsion (ETE) is an emulsion systemically delivering 0.05 mg of 17β-estradiol daily.

One dose consists of two packets to be applied once daily to the thigh and calf of both legs.

ETE uses a new technology (micellar nanoparticle emulsion) to systemically deliver estradiol, avoiding first-pass effects in the liver.

Mechanism of action

ETE works in a fashion similar to other transdermal estrogen-containing compounds.

Pharmacokinetic properties

The absolute bioavailability is 0.66% and the terminal exponential half-life is approximately 2.4 days.

The accumulation index is approximately 4, indicating sustained-release delivery.

Clinical efficacy

A 4-week, Phase II, randomized, double-blind, placebo-controlled, multicenter, dose-ranging study of 125 postmenopausal women with moderate or severe hot flashes found that 45% of women reported no moderate-to-severe hot flashes at week 4 with the approved dose of ETE compared with only 9% receiving placebo.

ETE was superior to placebo in reducing the frequency of hot flashes in a 12-week, randomized, double-blind, placebo-controlled clinical trial that included 200 postmenopausal women. This effect was observed by week 3 of treatment and was sustained for the remainder of the study.

The maximal reduction (85%) in frequency of hot flashes in patients receiving ETE was observed at week 12 (−11.1 ± 6.8 hot flashes/day compared with −7.2 ± 5.4 hot flashes/day for placebo; p < 0.001).

By 12 weeks, 68% of women in the ETE group reported 90% or greater reduction in vasomotor symptoms.

Safety & tolerability

ETE has been found to be safe and well tolerated; adverse events associated with its use in clinical trials are typical for estrogen-containing compounds as a class.

The most commonly reported adverse events included infection, endometrial disorders, breast pain, application site reaction, pruritus, vaginal bleeding and moniliasis.

References

Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers.

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Brett

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Vivelle® Prescribing Information. Novartis Pharmaceuticals Corp., NJ, USA (2004).

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EstroGel® Prescribing Information. Solvay Pharmaceuticals, Inc., GA, USA (2004).

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Estradiol Topical Emulsion for the Treatment of Moderate-to-Severe Vasomotor Symptoms Associated with Menopause

Abstract

Keywords

Currently available estrogen-containing therapies

Systemic estrogens

Local estrogens

Nonhormonal therapies

Estradiol topical emulsion

Chemistry

Pharmacodynamics

Pharmacokinetics & metabolism

Pharmacokinetics

Metabolism

Clinical efficacy

Phase II study

Phase III study

Safety & tolerability

Regulatory affairs

Conclusion

Future perspective

Information resources

References