A Review of Transdermal Nonpatch Estrogen Therapy for the Management of Menopausal Symptoms

Abstract

During the transition into menopause, women may experience a wide range of symptoms that negatively impact quality of life. The vasomotor symptoms (VMS) of hot flushes and night sweats are common and vary widely in frequency and severity. The treatment of menopause-associated VMS is a frequently encountered clinical challenge, with the goal of tailoring treatment for each individual woman's needs. Estrogen therapy is the most effective treatment for menopausal VMS. Current guidelines suggest that estrogen therapy be prescribed at the lowest effective dose for the shortest duration of time. Transdermal estrogen therapy has dominated the menopause prescribing practice in Europe for decades; however, in the United States, oral estrogen therapy is most commonly prescribed. Transdermal estrogen therapy can be prescribed at considerably lower doses than oral therapy yet has similar efficacy on the symptoms of menopause. Emerging research demonstrates transdermal estrogen, particularly 17β-estradiol, may have the potential for fewer health risks than oral estrogen therapy. This review article discusses the spectrum of menopausal symptoms, addresses prevailing issues in the treatment of menopause, elaborates on the risks and benefits of oral and transdermal hormone therapies, and focuses on five nonpatch transdermal estradiol therapies currently available in the United States.

Introduction

Historically, hormone therapy for the treatment of menopausal symptoms has been primarily administered orally; however, the past two decades have witnessed the introduction of a plurality of vehicles for transdermal estradiol administration. These new routes of delivery include creams, gels, lotions, patches, sprays, and vaginal rings. Clinical and experimental evidence suggests that compared with oral hormone therapy, transdermal estradiol therapy has an improved safety profile and a better treatment benefit/risk ratio. In view of the wide variety of choices in this class of therapy, this discussion specifically addresses nonpatch transdermal formulations to educate clinicians on this subset of hormone therapy.

This review article discusses the spectrum of menopausal symptoms and addresses prevailing issues in the treatment of menopause, including interindividual variability in dosing, the controversy around the Women's Health Initiative (WHI) initial data analyses, and bioidentical and compounded therapies. This article elaborates on the risks and benefits of oral and transdermal hormone therapies and the history of transdermal drug delivery and focuses on the nonpatch transdermal estradiol therapies currently available in the United States. The goal of this article is to enhance the clinical knowledge of hormone therapy options currently available for the treatment of the symptoms of menopause.

Spectrum of Menopause Symptoms and Therapeutic Options

Multiple comorbidities may arise from low estrogen levels in perimenopausal and postmenopausal women. Declining ovarian function may cause women to experience a wide spectrum of menopausal symptoms that vary in severity and duration. Common symptoms associated with menopause, which can affect quality of life in this population, include vasomotor symptoms (VMS) (hot flushes, night sweats), vulvovaginal atrophy (vaginal dryness, decreased lubrication and arousal, dyspareunia, urinary tract symptoms), hormonal headaches including migraines, psychological issues (mood changes, depression, cognitive issues), osteoporosis, and generalized symptoms (fatigue, insomnia, joint problems, skin changes).¹

As women transition from perimenopause to postmenopause, the most prevalent symptoms are vasomotor and vulvovaginal atrophic changes.¹ During the menopausal transition, up to 80% of women experience VMS;² although the prevalence of VMS varies across race and ethnicity.³ Data from the Study of Women Across the Nation (SWAN) suggests the prevalence of VMS is highest among African American women (80%) and lowest among women of Chinese and Japanese descent (55%).³

Whereas some women transition through menopause virtually asymptomatically, others experience mild symptoms not perceived as severe enough to warrant medical therapy. An additional group of women experience disruptive moderate to severe VMS requiring medical treatment. Within this group, a small subset has marked distress with severe VMS, which is sometimes accompanied by insomnia, anxiety or mood changes that may resemble an exacerbation of their premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD), or cognitive deterioration. Regardless, the majority of women experience VMS during a period that spans their late reproductive stage to years or decades past menopause.^4,5 When occurring in the daytime, VMS may be transiently disturbing, embarrassing, disconcerting, and accompanied by profuse sweating. When occurring at night, VMS are expressed as night sweats, which by disrupting sleep patterns may be associated with insomnia and fatigue.

Prevailing Issues in Menopausal Symptom Management

A host of exogenous factors contribute to the clinical management of menopausal symptoms, including influences of culture, religious beliefs, and research, most notably the results of the WHI clinical trials. Clinical practice, algorithms, and practice standards also are highly variable geographically. Treatment options can be influenced by prevailing economies, habit, patient preference, lack of awareness of options, and availability on third party formularies. For decades, oral therapies dominated the U.S. market; Europe and Australia have exhibited more interest in examining newer products, such as transdermal therapies for medical applications, including those for menopausal women.

Interindividual Variability in Estradiol Dosing

Effective management of the postmenopausal patient with hormone therapy is confounded by multiple pharmacological issues, such as timing of therapy initiation, type of therapy, route of administration, drug interactions with concomitant medications, body mass index (BMI), medical history, health habits, and genetics. During the reproductive years, each woman has wide-ranging estradiol levels dependent on the menstrual cycle phase. During the menopause transition, estradiol concentrations become unpredictable as a result of less frequent, arrhythmic cycling. When there are peaks and troughs in estradiol levels during the course of a day, women are more likely to be symptomatic because vasomotor flushes are correlated with low estrogen levels.^6
–8 As there is no absolute estrogen level below which vasomotor flushes occur, estrogen levels between symptomatic and asymptomatic women can be identical.^6,7,9 Because of this interindividuality, estrogen doses required to achieve consistent symptomatic relief differ for each woman. Current recommendations for hormone therapy from the U.S. Food and Drug Administration (FDA), North American Menopause Society (NAMS), and American College of Obstetricians and Gynecologists (ACOG) suggest the use of the lowest effective dose for the shortest duration of time, consistent with treatment goals, benefits, and risks for the individual woman. It is important to recognize that this applies to the individual patient and her symptoms at that point in time; therefore, dosing of hormone therapy should be based on the lowest effective therapy to achieve symptomatic relief for that individual.^10,11 Customizing each woman's dose and re-evaluating her treatment periodically are critical to effective hormone therapy management.

WHI Revisited: New Conclusions

Results from the WHI randomized trials raised concerns about the safety of estrogen treatment, alone or in combination with progestin. These trials were designed originally to investigate the protective effects of oral estrogen treatment against coronary heart disease (CHD), stroke, osteoporosis, and cancer in asymptomatic postmenopausal women. These trials were halted when it was shown that estrogen plus progestin therapy (conjugated equine estrogen/medroxyprogesterone acetate; Prempro™) was associated with increased risks of stroke, coronary events, pulmonary embolism, deep vein thrombosis, and breast cancer in women with intact uteri.^12,13 The estrogen only (conjugated equine estrogen; Premarin^®, Wyeth-Ayerst, Philadelphia, PA) arm of the trial was associated with an increased risk of deep vein thrombosis and stroke among women who had undergone hysterectomies, although not an increased risk of breast cancer.¹⁴

Since the release of the WHI results, many researchers and clinicians, including the principal investigators of the trials, have qualified the original conclusions.^15,16 The WHI trial evaluated only a standard dose (0.625 mg) of oral conjugated equine estrogens, and, thus, the WHI findings might be applicable to all estrogen therapies (i.e., lower doses, other types of estrogen, or different routes of administration).¹⁶ Additional randomized controlled trials (RCTs) are needed to confirm if there are differences in the physiological response to various treatment regimens. Furthermore, the majority of the subjects enrolled in the WHI trials were ≥ 10 years postmenopause, leaving the question unanswered as to whether similar risks would apply to perimenopausal or more recently postmenopausal women.

More recent subanalyses^17,18 and pooled meta-analyses¹⁹ of the WHI trials have shown that women who initiated hormone therapy between the ages of 50 and 59 or < 10 years postmenopause may be at lower risk of future cardiovascular events compared with women who initiated therapy later. Compared with the placebo group, the absolute numbers of women aged 50–59 years in the WHI study, who may be harmed by hormone therapy from cardiovascular events, were in the range of 0–1 additional case per 1000 women per year of hormone use, which defines those events as rare.²⁰ Taken together, these reports suggest that younger postmenopausal women may be able to use hormone therapy without increasing their risk of cardiovascular events.

It has been suggested that the age at which a woman uses hormone therapy may impact cognitive function. The WHI Memory Study (WHIMS), an ancillary study to the WHI, was designed to determine the effects of hormone therapy on the development and progression of dementia symptoms in postmenopausal women. The investigators found that memory declined in women ≥ 65 years who were using estrogen and progestin therapy.²¹ Although some animal and human trials have revealed a positive role of estrogens on the central nervous system (CNS) in areas of learning, mood, and cognition when initiated early in menopause,^22,23 many long-term clinical trials have failed to show these benefits.²⁴ Therefore, the inconsistencies in the results among the various studies warrant further investigation.

Controversies about Bioidentical and Compounded Therapies

Following the release of the WHI results, a large interest in developing more natural hormone therapies focused attention on bioidentical hormones. Natural and bioidentical are lay terms recently popularized by the media that have prompted large numbers of women to seek consultations with physicians who prescribe hormone therapy. Bioidentical hormones are defined as “derivatives of plant extracts chemically modified to be structurally indistinguishable from human endogenous hormones.”²⁵ According to this definition, bioidentical estrogens include 17β-estradiol, estrone, and estriol, which are synthesized from phytoestrogens found in Mexican yams, soybeans, and other plant sources.^25,26

Much of the confusion surrounding bioidentical hormones comes from the misconception that bioidentical hormones must be obtained by custom mixing (compounding) from a pharmacy; however, bioidentical hormones are also available as commercially manufactured FDA-approved hormone therapies. Custom-compounded bioidentical hormones are only available by prescription, but they have no approved package insert specifying efficacy or risk and do not require approval by the FDA.²⁷ Conversely, estradiol and progesterone products manufactured by pharmaceutical companies have a chemical structure identical to that of naturally produced hormones, undergo FDA approval to obtain specific indications for treatment, and are proven effective for the treatment of VMS.²⁸

Quality control, potency, and bioequivalence may also differ between compounded and manufactured bioidentical hormone therapies. Since 1996, the FDA has monitored ≥ 3000 manufactured pharmaceutical products from a variety of therapeutic categories. In that time, ≤ 2% of the manufactured pharmaceutical products failed in any tests, with only 4 failing potency tests. In contrast, in 2001, the FDA found a total of 34% of the compounded products tested failed ≥ 1 standard quality control test; of the compounded hormones, 25% failed potency tests.²⁹ To further explore these issues, the FDA conducted an additional survey of compounded drug products in 2006.³⁰ A total of 198 products from three major classes (female hormone products, inhalation products, and local anesthetic products) were surveyed; of these, 125 were active pharmaceutical ingredients (API) used in the compounding process (all of which passed laboratory analyses), and 73 were the finished compounded drugs. Of the 73 finished compounded drug products, 37 were excluded from analysis for various reasons (e.g., past expiration date), and 12 (33%) failed analytical testing. These results suggest that problems with the quality of compounded drugs may be directly related to the compounding process.³⁰ In 2005, ACOG issued an opinion stating there was “no scientific evidence supporting the claims of increased efficacy or safety for individualized hormone therapy prepared by compounding pharmacies.”³¹ Similarly, The Endocrine Society published a position statement supporting the FDA regulation of all hormones, including compounded hormones. The position statement urges surveys of purity and dose, inclusion of uniform information for patients with warnings and precautions, and the establishment of an adverse events registry regarding the use of compounded hormone preparations.³²

Risks and Benefits of Oral and Transdermal Estradiol Therapy

Administration of supraphysiological levels of oral estrogen is required to achieve therapeutic levels of circulating estradiol. This is because oral estrogen is extensively metabolized on first pass through the liver and causes nonphysiological levels of estrogen metabolites. Between 60% and 90% of the oral estrogen undergoes conversion into estrone and its conjugates.^33,34 Oral estrogens are more likely to have unacceptable side effects, such as postmenopausal bleeding or mastalgia,³⁵ as well as marked therapy discontinuation.³⁶

Transdermal estradiol avoids first-pass metabolism, allowing for more consistent and physiological estrogen blood levels. An early report by Powers et al.³⁷ found that transdermal estradiol treatment in postmenopausal women provided serum and urinary levels of estrogen and estrogen metabolites similar to those of the early follicular phase in premenopausal women. These results suggest that transdermal estradiol re-establishes the estradiol/estrone ratio to approximately 1.³⁷ Shifren et al.³⁸ reported an approximately 3-fold increase in the serum levels of estrone in women administered oral estrogen compared with transdermal estradiol, consequently reducing the estradiol/estrone ratio to < 1. The impact of the differences in the estradiol/estrone ratio between oral and transdermal administration on tolerability, safety, and efficacy is not clearly understood.

The use of transdermal and oral estrogen to treat symptoms associated with menopause has been studied extensively in clinical trials and further summarized in a recent systematic review and meta-analysis.^39,40 As the efficacy of oral and transdermal estrogen on the symptoms of menopause is similar,⁴⁰ it is important to review the different physiological effects of these two routes of administration. The route of administering estrogen therapy can have a differential effect on biomarkers. Inflammatory markers, fibrinolysis, and coagulation proteins are differentially altered with oral compared with transdermal estrogen. Similarly, insulin-like growth factor binding protein (IGFBP) and insulin resistance are elevated in women receiving oral hormone therapy.⁴¹ These differences are being investigated for their implications in chronic disease, such as diabetes and CHD;^42,43 however, the differences in these markers do not consistently predict outcomes in clinical trials.

Oral estrogen therapy favorably elevates high-density lipoprotein (HDL); although oral estrogen has also been implicated in elevating levels of markers for cardiovascular disease (CVD),⁴⁴ including C-reactive protein (CRP).⁴⁵ Oral estrogen may contribute to an increased risk for thrombogenesis by decreasing levels of antithrombin III, euglobulin clot lysis time (ECLT), plasminogen activator inhibitor-1 activity (PAI-1), tissue type plasminogen-activator antigen (tPA), and fibrinogen.⁴⁶ In 2007, the Estrogen and Thromboembolism Risk (ESTHER) study,⁴⁷ an observational/case-control study, suggested that oral estrogen increased the risk of venous thromboembolism (VTE) in postmenopausal women, although no risk of VTE was associated with the use of transdermal 17β-estradiol. This finding is in contrast to the increased risk of VTE found with the transdermal norelgestromin/ethinyl estradiol transdermal system. A recent meta-analysis of eight observational and nine RCTs investigated the risk of VTE in postmenopausal women receiving oral or transdermal estrogen.³⁹ These results further establish a role for oral estrogens in the increased risk of VTE, especially during the first year of hormone treatment and in women with a high BMI. In contrast to oral estrogen, transdermal estrogen does not appear to induce the cascade of hepatic protein synthesis. This cascade is hypothesized to be responsible for the observed differences in the risk of VTE between oral and transdermal routes of delivery. Consequently, transdermal estradiol may improve the benefit/risk ratio of hormone therapy, especially with respect to incidence of VTE.³⁹ Similarly, RCTs and meta-analyses have suggested that transdermal estrogen therapy may have less of an impact than oral estrogen therapy on serum triglycerides, lipoprotein profiles,^48
–50 and gallbladder disease.^51,52 The American Association of Clinical Endocrinologists (AACE) recommends transdermal hormone therapy in women with hypertension or hypertriglyceridemia or increased risk of cholelithiasis in their clinical guidelines.⁵³

History of Transdermal Drug Delivery

Traditionally, the epidermis has been regarded as a barrier protecting the body from outside influences; however, the epidermis can act as a conduit from the environment to the circulatory system. Transdermal delivery of nitroglycerine has been used in the United States since the 1950s for treatment angina pectoris.⁵⁴ More modern transdermal drug delivery (TDD) systems evolved during the late 1970s and 1980s, some of which include a scopolamine-releasing TDD system for the treatment of motion sickness, an isosorbide dinitrate-releasing TDD system for the once-daily treatment of angina pectoris, and an estradiol-releasing TDD system for treatment of postmenopausal symptoms.⁵⁵

The development of transdermal estradiol delivery systems evolved from an understanding of the pharmacokinetics and metabolism of oral estrogen. The intention was to develop a therapy that established physiological estradiol levels, produced fewer nonreactive metabolites, and decreased side effects, all while remaining efficacious.⁵⁶ Worldwide, the most used TDD systems for administering estradiol are patches and gels.²⁵ Estradiol patches are applied directly to the skin every 3½ or 7 days and deliver estradiol at a constant rate via percutaneous absorption. Within the last few years, nonpatch formulations of transdermal estrogen, which require daily application, have been developed that share the advantages of transdermal therapy but avoid inconveniences, such as skin reactions to adhesives, disadhesion, and visibility. Studies have shown no difference in absorption, bioavailability, or peak concentrations between patches and gels. In comparative studies, however, administration of estradiol by nonpatch transdermal therapies was found to maintain more consistent levels of serum estradiol than patch therapies.^57,58

Most of the nonpatch transdermal estradiol therapies are alcohol based; data confirm when alcohol-based estradiol products are applied, the alcohol quickly evaporates and estradiol accumulates subcutaneously and is gradually released into the systemic circulation.⁵⁹ One concern about nonpatch transdermal estrogen formulations is the possibility of skin-to-skin transfer of estradiol to others; however, recent publications have affirmed the risk of interindividual transfer of estradiol to be minimal.^60
–62

Nonpatch Transdermal Estrogen Therapies

Currently, five nonpatch, transdermal estrogen therapies are available in the United States—estradiol gel (Elestrin™, BioSante, Lincolnshire, IL) estradiol gel 0.06% (Estrogel^®, Ascend, Herndon, VA), estradiol gel 0.1% (Divigel^®, Upsher-Smith, Minneapolis, MN), estradiol transdermal spray (Evamist™, Ther-Rx, St. Louis, MO), and estradiol topical emulsion (Estrasorb^®, Graceway, Bristol, TN)—for treatment of vasomotor symptoms in hysterectomized women or in combination with a progestin for women with an intact uterus. Although each product contains the same bioidentical estrogen (17β-estradiol), there are significant differences in formulation, application, available dosing options, and systemic estradiol delivery (Table 1). The following section describes these nonpatch options for transdermal estrogen therapy and provides a summary of efficacy (Figs. 1 and 2) and safety (Table 2) of these products. Currently, no generic alternative of these products exists, and a concurrent progestin therapy is needed with each nonpatch transdermal estrogen therapy in women with an intact uterus, as no nonpatch transdermal combination therapy is currently available.

FIG. 1.

Change from baseline in daily frequency of moderate to severe VMS (MSVMS). *p ≤ 0.05 vs. placebo; **p ≤ 0.01 vs. placebo; ^† p ≤ 0.001 vs. placebo; data presented as mean or median.

FIG. 2.

Change from baseline in daily severity of moderate to severe VMS (MSVMS). *p ≤ 0.05 vs. placebo; **p ≤ 0.01 vs. placebo; ^† p ≤ 0.001 vs. placebo; data presented as mean or median.

Table 1.

Properties of Nonpatch Transdermal Estradiol Therapies ^a

Name	Estradiol gel	Estradiol gel 0.06%	Estradiol gel 0.1%	Estradiol transdermal spray	Estradiol topical emulsion
Formulation	0.52 mg E₂ ^b/0.87 g alcoholic gel	0.75 mg E₂/1.25 g alcoholic gel	1 mg E₂/1 g alcoholic gel	1.53 mg E₂/90 μL alcohol and octisalate solution	2.5 mg E₂ hemihydrate/1 g micellar nanopartical technology
Supplied	Metered dose pump	Metered dose pump	Unit dose foil packets	Metered dose spray	Unit dose foil pouch
Metered or unit dose(s)	0.87 g gel/pump	1.25 g gel/pump	0.25 g, 0.5 g, or 1.0 g gel/packet	90 μL solution/spray	1.74 g emulsion/pouch
Application	By hand to upper arm and shoulder	By hand to arm, from wrist to shoulder	By hand to upper thigh	By spray to inner arm	By hand to entire thigh and calf
FDA-approved dose(s)	1 pump (0.87 g)		0.25 g packet	1 spray (90 μL)
	2 pumps (1.7 g)	1 pump (1.25 g)	0.5 g packet	2 sprays (180 μL)	2 pouches (3.48 g)
			1.0 g packet	3 sprays (270 μL)
C_avg on day 14	15.4 pg/mL (1 pump)		9.8 pg/mL (0.25 g)	19.6 pg/mL (1 spray)
	39.2 pg/mL (2 pumps)	28.3 pg/mL (1 pump)	21.0 pg/mL (0.5 g)	30.7 pg/mL (2 sprays)	58.6 pg/mL^c (2 pouches)
			30.5 pg/mL (1.0 g)	30.9 pg/mL (3 sprays)
Systemic E₂/day	12.5 μg (1 pump)		3.4 μg (0.25 g)⁶⁵	21 μg (1 spray)⁶⁶
	37.5 μg (2 pumps)	35.1 μg (1 pump)⁷⁰	8.8 μg (0.5 g)⁶⁵	29 μg (2 sprays)⁶⁶	50 μg (2 pouches)
			27.3 μg (1.0 g)⁶⁵	40 μg (3 sprays)⁶⁶

Data provided from prescribing information accessed October 2008.

E₂, estradiol.

C_min on day 14.

Table 2.

Frequency (%) of Adverse Events Reported in ≥ 5% of Subjects in Any Active Treatment Group ^a

	Estradiol gel		Estradiol gel 0.06%	Estradiol gel 0.1%			Estradiol transdermal spray			Estradiol topical emulsion
	0.87 g	1.7 g	1.25 g	0.25 g	0.5 g	1.0 g	1 spray	2 sprays	3 sprays	3.45 g
Reproductive system and breast disorders
Mastalgia^b	6.6%	7.7%	12.5%	2.5%	5.7%	8.8%	7.9%	13.5%	6.6%	10.1%
Postmenopausal bleeding	4.4%	9.2%	4.2%	4.1%	5.7%	9.6%	NR^c	NR	NR	NR
Endometrial disorder	NR	NR	1.8%	NR	NR	NR	NR	NR	NR	15.1%
Vaginitis^d	NR	NR	8.9%	0.8%	2.4%	6.4%	NR	NR	NR	NR
Suspicious Pap smear	NR	NR	5.4%	NR	NR	NR	NR	NR	NR	NR
Other
Infection^e	16.2%	12.0%	17.3%	11.5%	6.5%	6.4%	5.3%	4.1%	1.3%	17.9%
Headache	NR	NR	20.2%	NR	NR	NR	9.2%	12.2%	10.5%	8.6%
Pain^f	NR	NR	19.6%	NR	NR	NR	2.6%	5.4%	2.6%	NR
Nausea	NR	NR	6.0%	NR	NR	NR	1.3%	2.7%	2.6%	NR
Pruritus^g	NR	NR	11.9%	NR	NR	NR	NR	NR	NR	3.5%
Flatulence	NR	NR	6.5%	NR	NR	NR	NR	NR	NR	NR
Flu syndrome	NR	NR	5.4%	NR	NR	NR	NR	NR	NR	NR

Data from prescribing information accessed October 2008.

Includes nipple pain.

NR, not reported.

Includes vaginal mycosis.

Includes upper respiratory infection, nasopharyngitis, sinusitis, rhinitis, common cold, and eye infections.

Includes abdominal and back pain.

Includes rash.

The data provided in this summary were taken from individual clinical trials with different study design and individual study populations; therefore, data provided in this summary cannot be used to compare the individual treatments. This summary is not meant to directly compare the individual treatment options, as no comparative studies have been conducted. The information provided here is meant to assist clinicians in individualizing estrogen therapy for their patients by providing all information on the nonpatch transdermal estrogen therapies in a concise summary.

The data presented were obtained from current FDA-approved prescribing information (PI) for each product from the American manufacturer's websites (accessed in October 2008).^63

–67 When necessary, data not provided in the PI were obtained from the literature.

Overview of Nonpatch Transdermal Estrogen Therapies

Estradiol gel

Estradiol gel contains 0.06% 17β-estradiol in an alcoholic gel base supplied in a metered-dose pump (Table 1). Each pump delivers a dose of 0.87 g gel containing 0.52 mg estradiol. Estradiol gel is applied once daily to the upper arm and shoulder over an area approximately 320 cm². The U.S. FDA approved two doses in 2006 for the treatment of moderate to severe VMS associated with menopause: 0.87 g (1 pump) and 1.7 g (2 pumps), containing 0.52 mg and 1.04 mg estradiol, respectively. One pump (0.87 g) of estradiol gel delivers 12.5 μg systemic estradiol; 2 pumps of estradiol gel delivers 37.45 μg systemic estradiol.

Estradiol gel 0.06%

Estradiol gel 0.06% contains 0.06% 17β-estradiol in a hydroalcoholic gel base. In the United States, only one dose (1.25 g) of estradiol gel 0.06% has been approved by the FDA. Estradiol gel 0.06% is supplied in a metered-dose pump (Table 1); 1 pump dispenses 1.25 g estradiol gel 0.06%. This dose contains 0.75 mg estradiol, which delivers 35.1 μg systemic estradiol. The gel is applied to the arm, from the wrist to the shoulder over an area approximately 750 cm².

Estradiol gel 0.1%

Estradiol gel 0.1% is an alcohol-based gel containing 17β-estradiol. In the United States, there are three FDA-approved dosages indicated for the treatment of moderate to severe VMS: 1 g, 0.5 g, and 0.25 g gel, containing 1 mg, 0.5 mg, and 0.25 mg estradiol, respectively. Estradiol gel 0.1% is supplied in a single, daily dose foil packet (Table 1), which is applied to an area of skin of approximately 200 cm² (5 × 7 in) on the upper anterior thigh. Once daily application of estradiol gel 0.1% delivers approximately 3.4 μg (0.25 g), 8.8 μg (0.5 g), or 27.3 μg (1.0 g) of systemic estradiol.⁶⁸

Estradiol transdermal spray

Three doses of estradiol transdermal spray were approved by the FDA in 2007 for the treatment of moderate to severe VMS. Estradiol transdermal spray is a homogeneous liquid solution of 1.7% estradiol in alcohol and octisalate that is supplied in a glass vial fitted with a metered-dose pump (Table 1). The pump is encased in a plastic hand-held device that controls the distance, angle, and area of application for each metered dose spray. Each spray delivers 90 μL solution containing 1.53 mg estradiol to an area on the inner surface of the arm between the elbow and wrist. One, two, or three sprays are applied daily to nonoverlapping areas of the inner arm for treatment of moderate to severe VMS associated with menopause. One spray contains 1.53 mg estradiol and delivers 21 μg systemic estradiol; two sprays contain 3.06 mg estradiol and deliver 29 μg systemic estradiol; three sprays contain 4.59 mg estradiol and deliver 40 μg systemic estradiol.⁶⁹

Estradiol topical emulsion

Estradiol topical emulsion was designed to deliver estradiol to the blood circulation after topical application. Each gram of estradiol topical emulsion contains 2.5 mg estradiol hemihydrate, which is encapsulated using a micellar nanoparticle technology. Estradiol topical emulsion is packaged in foil pouches containing 1.74 g (Table 1). One dose (3.48 g lotion [2 foil pouches]) of estradiol topical emulsion has been approved by the FDA. One daily dose of estradiol topical emulsion contains a total of 8.7 mg estradiol and delivers 50 μg systemic estradiol. The two foil pouches are applied by rubbing the emulsion into the skin of the entire thigh and calf, one pouch to each leg, for 3 minutes.

Efficacy of Nonpatch Transdermal Estrogen Therapies

In separate clinical trials, each of the nonpatch transdermal estrogen therapies significantly reduced both frequency (Fig. 1) and severity (Fig. 2) of moderate to severe VMS by week 12 compared to placebo. As these data were taken from separate clinical trials, they are not meant to be used as a direct comparison between treatments. Rather, these data provide information about the efficacy of each individual therapy and may be used as a tool for prescribing nonpatch transdermal estrogen therapy.

Each dose of each individual treatment significantly reduced the frequency of moderate to severe VMS compared with placebo. Similarly, all therapies described here exhibited a significant decrease in the severity of moderate to severe VMS compared with placebo. Finally, of the three products with more than one approved dose, estradiol gel and estradiol gel 0.1% demonstrated an approximate dose-response in the reduction of both frequency and severity. Although all doses of estradiol transdermal spray were efficacious in reducing the frequency and severity of moderate to severe VMS compared with placebo, a dose-response trend was not observed.

Safety and Tolerability of Nonpatch Transdermal Estrogen Therapies

All the products described in this summary were found to be safe and well tolerated. All estrogen therapies, however, including nonpatch transdermal therapies, carry the standard FDA class warning related to breast and endometrial cancer, CVD, and other health risks associated with the use of estrogen. The treatment-emergent adverse events reported in ≥ 5% of subjects in any active treatment group for each therapy are detailed in Table 2. As previously stated, these data were taken from separate clinical trials with separate study populations and trial designs and should not be used as a direct comparison between treatments; however, these data can provide a basis for identifying adverse events specific to each treatment.

Breast tenderness was the only reproductive system and breast disorder adverse event reported in ≥ 5% of patients in all therapies; infections were also reported in ≥ 5% of patients in all therapies. Estradiol gel 0.06% (1.8%) and estradiol topical emulsion (15%) were the only treatments with any reported endometrial disorder. Reports of skin reactions at application site were low for all treatments; only a small percentage of estradiol gel-treated patients (1%–4%) reported skin reactions at the application site.⁷¹ This percentage was even lower in women treated with estradiol transdermal spray (1.3%) or estradiol gel 0.1% (< 1.0%). No information was available for application site reaction for either estradiol gel 0.06% or estradiol topical emulsion.

Conclusions

Nonpatch transdermal estrogen products, such as gels and sprays, are effective alternatives to oral estrogen therapy. These therapies offer a wide variety of treatment doses, provide more consistent blood levels of estrogen than oral therapies, and avoid first-pass hepatic metabolism. Transdermal estrogen therapy may be more appropriate for patients with certain medical conditions, including hypertension, hypertriglyceridemia, and increased risk of cholelithiasis. Future RCTs should assess the potential benefits of transdermal estrogen therapy in providing an improved safety profile. Taken together, the nonpatch transdermal estradiol therapies enhance the number of available treatment options available to healthcare providers in the care of menopausal women.

Footnotes

Acknowledgments

I acknowledge Regina Switzer, Ph.D., for her extensive editorial assistance financially supported by Upsher-Smith Laboratories, Inc.

Disclosure Statement

N.C. is a member of the speaker bureaus and advisory boards for Upsher-Smith Laboratories, Inc., and Warner-Chilcott.

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