Intravaginal Drug Delivery Systems to Treat the GSM

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Intravaginal Drug Delivery Systems to Treat the Genitourinary Syndrome of Menopause: Towards the Design of Safe and Efficacious Estrogen-loaded Prototypes (2023)
Ahmed Abdelgader, Mershen Govender, Pradeep Kumar, Yahya E. Choonara


Estrogens locally delivered to the vagina by tablets, capsules, rings, pessaries, and creams are the most common and highly recommended platforms to treat the genitourinary syndrome of menopause (GSM). Estradiol, an essential estrogen, is routinely administered alone, or in combination with progestins, to effectively alleviate the symptoms associated with moderate to severe menopause when non-pharmacological interventions are not indicated. Since the risk and side effects of estradiol use depend on the administered amount and duration of use, the lowest effective dose of estradiol is recommended when long-term treatment is required. Although there is a wealth of data and literature comparing vaginally administered estrogen-containing products, there is a lack of information revealing the effect of the delivery system used and formulation constituent’s attributes on the efficacy, safety, and patient acceptability of these dosage forms. This review, therefore, aims to classify and compare various designs of commercially available and noncommercial vaginal 17b-estradiol formulations and analyze their performance in terms of systemic absorption, efficacy, safety, and patient satisfaction and acceptance. The vaginal estrogenic platforms included in this review are the currently marketed and investigational 17b-estradiol tablets, soft gel capsules, creams, and rings for the treatment of GSM, based on their different design specifications, estradiol loads, and materials used in their preparation. Additionally, the mechanisms of the effects of estradiol on GSM have been discussed, as well as their potential impact on treatment efficacy and patient compliance.


The genitourinary symptoms experienced during menopause are broad and include a number of physiological processes that often result in dryness of the vagina, pain during intercourse, urinary inconsistency, and hot flashes.1 In 2014, the term genitourinary syndrome of menopause (GSM) was introduced for the first time, replacing the terms vulvovaginal atrophy, vaginal atrophy, and urogenital atrophy, with both postmenopausal and premenopausal women affected by this condition. However, GSM has been noted to be more prevalent in postmenopausal women,2,3 with more than 50% experiencing at least one of the above-mentioned symptoms.4-7 Despite the high prevalence and availability of treatments for GSM, these conditions are often under-diagnosed and ineffectively treated for several reasons including the unwillingness of women to discuss the symptoms with their healthcare provider, a lack of education regarding the condition and its treatments, women not recognizing that their experienced symptoms relate to estrogenic deficiency, and many healthcare practitioners not assessing their patients for GSM symptoms.8-10

The initial aim of treating GSM symptoms is to lessen and eliminate the experienced symptoms.3 Numerous treatment options are available for GSM and can be classified into non-hormonal therapy and hormone replacement therapy. Non-hormonal therapy is considered the first-line treatment for mild symptoms and includes vaginal lubricants and moisturizers. Recently, ospemifene, laser therapy, and radio frequency-based therapy are also being used as new alternatives when estrogenic therapies are not recommended. It is routinely only when severe and persistent symptoms are experienced, and non-hormonal therapy is not as effective, that hormonal treatment, including estrogen-containing medications, are introduced. They are considered the "gold standard" pharmacological treatment and the most effective therapy since they act directly towards the cause of GSM; the lack of estrogen.1,3,11

Several routes of administration are used for delivering estrogen-containing medications, including vaginal, oral, or transdermal routes.3,12
Oral and transdermal delivered estrogens, however, face numerous problems and limitations, such as first-pass metabolism, the need for frequent administration, and unsteady estrogen plasma concentrations.13 The vaginal route, however, exhibits superior outcomes than other routes; due to the vagina possessing a mucous membrane with a large surface area, an abundance of blood vessels, bypassing first-pass hepatic metabolism, and the ability to retain a high amount of drug locally.3,14-17 Using estrogen-containing medications, mainly through the vaginal route, also leads to the restoration of the vaginal cytology with increased superficial cells, raised vaginal blood flow and fluid secretions, maintenance of the microbiological balance of the vagina, reduced pH, increased resistance of the vaginal cell to infection and inflammation, and as a consequence, improvement in GSM symptoms.9,18,19

Drug distribution throughout the vaginal tissue differs noticeably from the attributes of the delivery system, with the selection of the vaginal delivery system often relying on the intended effect of treatment.
Drug retention at the mucosal surface with even distribution and low mucosal penetration is favored for local effects, while a systemic effect could be obtained via controlled extended drug absorption through the vaginal epithelium. Semi-solid systems are also desirable for local effects because they distribute evenly in the vaginal cavity and are bio-adhesive, while vaginal ring systems are more suitable for topical effects.17,20 Various vaginal estradiol preparations are currently on the market and are in use for the local treatment of GSM, including creams (Estrace®), tablets (Vagifem®), and vaginal rings (Estring® and Femring®), which besides their local effects, also exert systemic effects and are used in the treatment of hot flashes.21,22

Although estradiol vaginal delivery systems have been revealed to be efficient, they differ in their components and there are concerns about the properties of some of these systems. These vaginal preparations, additionally, have several limitations and drawbacks, such as messiness, a need for an applicator, low retention times, and frequent insertions required for tablets and creams.23-31 Furthermore, the rings are invasive during their insertion and removal, may dislodge, and have problems associated with the initial burst release,32 and though the performances of the vaginally-administered estrogen platforms in terms of efficacy, safety, and tolerance have been thoroughly researched, there is limited data correlating this performance to their design attributes. Therefore, the purpose of this review is to describe and compare various vaginal 17b-estradiol formulations based on their design specifications, loaded amount of estradiol, and carrier, as well as to evaluate their performance in terms of systemic absorption, efficacy, safety, and patient acceptability.

Pathophysiological Considerations of GSM for Intravaginal System Design

GSM depicts the wide range of changes that occur due to the decreased level of estrogen associated with menopausal transition,1,3,11,12,33 or due to an iatrogenic estrogen deficiency during reproductive age resulting from external factors, such as drug use, oophorectomy, and cancer treatment.34 This decreased level of estrogen leads to a breakdown of collagen and elastin fibers, resulting in genital changes such as the loss of elasticity, labia minora fading, labia majora shortening, narrowing of the introital opening, vaginal shrinkage and a narrowing and thin-pale vaginal epithelium.19,34 Also, the decline of estrogen level is associated with the reduction of blood flow to the vagina, causing less exudation and lubrication during sexual arousal and consequently resulting in dyspareunia and postcoital bleeding.19 In addition, glycogen production decreases with the diminished estrogen level, leading to increased pH and imbalance of the normal vaginal microflora, resulting in an increased risk of urinary tract infections.19,35 The gynecological, urological, and sexual signs and symptoms associated with GSM are illustrated in Fig. 1. In general, GSM develops later than the other symptoms of menopause and does not begin until the amount of endogenously produced estrogen is significantly lower than that is essential for endometrial stimulation.36,37 At this phase of menopause, there is a therapeutic index (Fig. 2) during which it is probable to combat genitourinary atrophy by using lower doses of estrogen than that normally prescribed, without hazardous endometrial hyperplasia.36

Menopause-specific Factors Affecting Drug Absorption from the Vagina

The onset of menopause has numerous effects on the absorption of drugs, not only in the treatment of menopause. Drug absorption from the vagina occurs in two major steps: i) drug dissolution within the vaginal cavity, and ii) permeation through the vaginal membrane, which occurs by the transcellular or paracellular pathways. Thus, any elements that influence these steps may impact drug absorption patterns from the vagina.17,20 These elements may include formulation characteristics, physicochemical properties of the drug and the excipients used, and the physiological features of the vagina.17,38

*Aligned Physicochemical Properties of Drugs and Excipients for Intravaginal Delivery

*Salient Physiologic Features for Optimal Intravaginal Drug Absorption

*Vaginal Fluid Volume and pH

*Vaginal Tissue Dynamics

*Enzymatic Activity

Factors Influencing GSM Severity and Response to Therapy

Demographic factors have been noted to potentially influence the degree of GSM symptom severity, as well as age and body mass index. It is recognized that the proceeding in age leads to lessening estrogen levels, in contrast to an increase in body mass index which leads to an increase in circulating estrogen. Hence, alteration in such factors would expect a change in the severity of GSM symptoms and their response to treatment.52

Current Estradiol-loaded Vaginal Drug Delivery Systems

The vagina is an important site for local and systemic drug delivery and is considered an effective alternative route to deliver drugs with poor oral bioavailability.24,55 Vaginal delivery furthermore reduces systemic adverse effects and offers local drug accumulation.56 It also demonstrates numerous other benefits such as self and easy administration, high permeability, and a large perfusion surface area.15,56,57 One clinical challenge associated with vaginal dosage forms, however, is patient perspective, as many patients fear that the formulation will be washed out.58 Traditionally, the vaginal route has been employed to deliver hormones and anti-infective agents such as antivirals, antifungals, and antibacterials, in different dosage forms.23,57 Currently, various delivery systems for both local and systemic action are available on the market or in clinical development. These systems include classical dosage forms including creams, ointments, pessaries, tablets, and capsules. Recently, novel formulations such as films and vaginal rings have also been developed.15,25,59 Low-dose vaginal estrogen-loaded formulations have also been extensively used due to their avoidance of hepatic metabolism and a greater respond-ability of vaginal tissues from the locally applied estrogen, making these systems considered to be more efficient than systemic delivery in the alleviation of GSM.60-62 Estradiol-based pessaries and creams were the first vaginal formulations effectively used in relieving the urogenital symptoms of menopause, but they are rarely used for extended treatment duration.

The choice of the delivery system is therefore highly dependent on the patient's preferences and needs.63 The dose regimen for the rings is that one ring is inserted vaginally for three months while dosing for creams and tablets consists of starting with a daily application for two weeks, as a loading dose, followed by applications twice per week as a maintenance dose for the period needed to control symptoms.7,64 The underlying rationale for this schedule is that during the initial days of therapy, the vaginal epithelium is atrophic, leading to high estradiol absorption. The vaginal epithelium subsequently matures with estradiol use and time, resulting in decreased absorption; hence, smaller doses are usually required to provide adequate estradiol accumulation to avoid vaginal atrophy recurrence.64 Table 1 shows the FDA-approved vaginal estradiol delivery systems, their excipients, estradiol loads, release rates, and their dose regimens, while Table 2 summarizes studies that compare test estradiol vaginal formulations versus placebos, or other vaginal estrogen formulations.

*Vaginal Tablets
-Safety of Vaginal Tablets

*Softgel Capsules
-Safety of Softgel Capsules

*Vaginal Rings
-Safety of Vaginal Rings

*Vaginal Creams
-Safety of Vaginal Creams

Advanced Estradiol Drug Delivery Systems for Menopausal Symptoms

With a large number of developed and marketed oral tablets, vaginal rings, and creams, advanced platforms have been researched to enhance patient treatment, safety, and acceptability. Hormonal replacement therapy has also been investigated to be delivered through various routes including orally, nasally, dermally, vaginally, and intramuscularly, where the dose regimen could be customized to each patient.153 The availability of versatile polymers and their incorporation into drug delivery systems has also made a remarkable advance in this field of research. Several of these polymers have been employed in the formulation of vaginal delivery systems to address practical challenges such as leakage and imparting sustained controlled release.17 Other systems have additionally been developed for the delivery of estradiol topically. Estradiol transdermal spray solutions are considered appropriate delivery systems for the alleviation of menopausal symptoms, especially for women with diabetes mellitus hypertriglyceridemia and those with altered liver function. These delivery systems offer better bioavailability, steady estrogen levels, and estradiol/estrone ratio over extended periods of time and are associated with low adverse events compared to oral estrogen.153 Additionally, the transdermal spray delivery systems are free of shortfalls related to traditional transdermal estradiol delivery systems.154 One novel transdermal spray solution is Lenzetto® (Gedeon Richter Plt., Hungary) which contains 1.53 mg of estradiol per 90 ml one spray dose.153,154 The Lenzetto spray container contains 95% ethanol, octisalate (as a skin-penetrating agent), in addition to the 17bestradiol. The application of the dose is controlled to the specific area by using a plastic housing, which is controlling the angle and distance of the sprier from the surface of the skin.154

Additionally, in a study by Krizman et al., 45 the practicability of silk fibroin xerogels as an implantable drug delivery system for continuous controlled-released estradiol delivery in hormone replacement therapy was investigated. The system exhibited sustained in vitro release for more than four months (Fig. 7) and had a biodegradation pattern suitable for the extended-term delivery of estradiol. The system could also offer an attractive alternative to conventional systems and could be useful in future clinical applications. These systems, while not administered vaginally, have shown the increased potential of developing advanced drug delivery platforms for the treatment of GSM.

Future Perspectives

Although there is significant research data and reports studying and evaluating vaginal estradiol delivery systems, there is limited research data evaluating and comparing the Estrace® vaginal cream with other vaginal estrogens preparations. Future studies are also needed to elucidate the pharmacokinetics, efficacy, safety, and patient acceptability of the Estrace® vaginal cream. Additionally, there is a need for studies of more than one year to evaluate the safety of vaginal estradiol delivery systems for long-term use.

Currently available vaginal estradiol delivery systems have been shown to be equally effective in alleviating GSM symptoms, however, there are still some challenges and limitations which must be overcome. Creams need an applicator for use, are messy, leaky, and associated with excessive discharge, while tablets may remain intact or not completely dissolved. Creams, tablets, and capsules additionally require repeatable insertions or applications. Rings are designed to have a controllable release of estradiol over three months but may dislodge and their insertion and removal may be difficult and requires a trained healthcare practitioner. These challenges could lead to decreased levels of patient comfort and, as a consequence, treatment adherence reduces over time.
Hence, a delivery system based on suitable materials, free of limitations, and administered less frequently, can ensure increased patient acceptability and greater control and treatment of GSM.


GSM is a common, chronic, under-diagnosed, and under-treated condition due to decreased estrogen levels throughout menopause. The treatment of GSM should be continued for extended periods of time as long as the condition persists. Local vaginal low-dose estrogen therapies are employed for the treatment of mild to severe GSM when over-the-counter therapies fail to control symptoms. A variety of pharmaceutical delivery systems of low-dose estradiol in the form of tablets, soft gel capsules, creams, and rings are approved and available and are in use for the site-specific release of estradiol to vaginal tissues. These products, with the exception of the vaginal rings which are applied every three months, are administered locally in a complicated dose regimen, where multiple administrations are often required per week. All forms are effective and provide rapid improvement in the subjective and objective symptoms of GSM, but not the vasomotor symptoms, except when using the high-dose Femring®. Additionally, most local estradiol-containing formulations exhibit negligible to low systemic estradiol exposure in levels that do not exceed the normal postmenopausal range. This low absorption of estradiol, associated with non-significant differences compared to a placebo in the incidence of endometrium stimulation, is free of the risk of serious side effects of systemic estrogen treatment. The choice of a particular local estradiol delivery system, however, is highly determined by the patient’s acceptability and preference, and this should be considered in the development of future pharmaceutical systems for the treatment of GSM.


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Figure 1. The common clinical manifestations of GSM.
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Figure 2. Therapeutic index during which it is probable to combat GSM using lower doses of estrogen. Reproduced with permission from Samsioe36 1998 Mosby, Inc
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Table 2 Summary of the studies that compared test estradiol vaginal formulations versus placebos, or to other vaginal estrogen formulations.
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Figure 3. Reasons for switching from a vaginal cream to a vaginal tablet. Reproduced from Minkin et al.63, 2013 Minkin et al, publisher and licensee Dove Medical Press Ltd.
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Figure 4. Linear plot of a baseline-corrected mean plasma concentration versus time for (a) estradiol, (b) estrone, and (c) estrone sulfate after treatment with the test and reference preparations, each at (A) 10mg and (B) 25mg. Test product: TX-004HR; TherapeuticsMD, Inc., Boca Raton, FL. Reference product: Vagifem®; Novo Nordisk, Plainsboro, NJ. Reproduced from Pickar et al. 123 2016 J. H. Pickar.
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Figure 5. Treatment preference over previously used vulvar and vaginal atrophy treatments. P value versus placebo. Reproduced from Kingsberg et al.120, 2017 The Author(s).
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Figure 6. Images of the FDA-approved vaginal rings for hormone replacement therapy (Estring® and Femring®) adapted from Zhao et al.134 The Author(s) 2022.
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Figure 7. (a) Morphology of silk fibroin hydrogel (left) and xerogel (right) samples with estradiol; in vitro release profiles of estradiol from xerogel delivery systems in (b) non-sink and (c) sink conditions (arithmetic means and standard deviations of n = 3). Adapted with permission from Krizman et al.45 2021 Elsevier B.V.
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