Treatment of vaginal atrophy with estriol and lactobacilli combination: a clinical review

Abstract

In recent years, a vast quantity of clinical data has been accumulated on the pathophysiology of symptomatic vulvovaginal atrophy (VVA)/genitourinary syndrome of menopause (GSM) in peri- and postmenopausal women and on the treatment options for these conditions. Guidelines from several societies have recently been updated in favor of VVA/GSM vaginal therapy with the lowest possible doses of estrogens. The combination of a vaginal ultra-low dose of 0.03 mg of estriol (E3) and lyophilized, viable Lactobacillus acidophilus KS400 (0.03 mg-E3/L) is a unique product with a dual mechanism of action supporting not only the proliferation and maturation of the vaginal epithelium, but also restoration of the lactobacillary microflora. It has been demonstrated efficiently to establish and maintain a healthy vaginal ecosystem. Use of this combination considerably improves the clinical signs and symptoms as well as the quality of life of menopausal women suffering from vaginal atrophy. This combination therapy is well tolerated with a low overall incidence of side-effects and negligible estriol absorption. Based on recent scientific evidence and current treatment guidelines, the 0.03 mg-E3/L combination could be considered one of the options for the treatment of symptomatic vaginal atrophy in aging menopausal women.

Keywords:

• Vaginal atrophy
• genitourinary syndrome of menopause
• vaginal estriol
• vaginal lactobacilli

Introduction

In recent years, a vast quantity of clinical data has been accumulated on vaginal atrophy issues. According to the International Menopause Society (IMS), up to 40% of postmenopausal women will experience urogenital atrophy¹. However, only 25% of symptomatic women are actively seeking treatment, and 70% report that their physician rarely asks about vaginal symptoms¹.

Various terms have been traditionally used to describe this medical condition: vulvovaginal atrophy (VVA), urogenital atrophy, (symptomatic) vaginal atrophy and atrophic vaginitis, etc. New terminology was recently proposed by American scientific societies (the North American Menopause Society (NAMS) and the International Society for the Study of Women’s Sexual Health) to describe the complexity of typical urogenital signs and symptoms, namely genitourinary syndrome of menopause (GSM)^2,3.

The current treatment options for VVA/GSM such as the use of low-dose estrogen or an ultra-low dose of estriol (E3), with or without lactobacilli combination, have been described⁴. The aim of this article is to review available scientific knowledge on the use of ultra-low-dose estriol (0.03 mg-E3) and Lactobacillus acidophilus KS400 (L) combination (0.03 mg-E3/L) and to provide state-of-the-art evidence for clinicians facing urogenital atrophy problems in aging women.

Vulvovaginal atrophy/genitourinary syndrome of menopause

Pathophysiology overview

For the normal functioning of the balanced vaginal ecosystem, sufficient estrogen levels leading to an intact vaginal epithelium as well as healthy microflora (vaginal microbiome) are essential^1,5,6. The immune response also influences this ecosystem⁷.

The defensive vaginal lactobacillary flora is in a dynamic state. The abundance and bacterial type composition can change rapidly⁶. Beneficial lactobacilli produce various antibacterial compounds⁵, can compete with pathogens for adherence (competitive exclusion), and interact with the local immune mechanisms in the vagina. Interestingly, estrogen levels also play a crucial role in maintaining lactobacilli-dominated flora⁸.

Another basic element in the micro-ecology of the vagina is the stratified, squamous non-keratinized vaginal epithelium consisting of basal, parabasal, intermediate and superficial cell layers. The female sex hormones regulate the development and functioning of sex organs, supporting and maintaining vaginal elasticity and lubrication in particular. Thus, the development of the epithelium is related to circulating estrogen levels and varies depending on physiological conditions. Due to the high affinity of estrogen molecules for estrogen receptors (ERs), only a low dose of hormone is needed to generate sufficient effect⁹. A vaginal epithelium stimulated by estrogen is a prerequisite for establishing and maintaining physiological flora^10,11. The breakdown of proliferated superficial cells liberates glycogen, which serves as a substrate for the lactobacilli¹².

Urogenital atrophy is characterized by the changes in the urogenital tract due to a marked decrease in ovarian estrogen production¹⁰. Serum estrogen levels normally range from 40 to 400 pg/ml in premenopausal women, decreasing to less than 20 pg/ml during the postmenopausal period¹³. The usual underlying cause of estrogen deficiency is natural menopause, but this can also be triggered by lactation and premature ovarian insufficiency (POI). Interventions that indirectly reduce ovarian function, such as radiotherapy or tamoxifen therapy, may also cause atrophy. Heavy smokers might also be affected^14,15. The change in circulating estrogen levels is reflected in changes in vaginal physiology and symptoms, resulting in decreased barrier and lubrication functions of the epithelium, lower vaginal glycogen content, the presence of lactobacilli and increased penetration by pathogens, often culminating in atrophic vaginitis^1,16.

Diagnostic considerations

Women are generally unaware of the fact that VVA can have a significant impact on sexual health or that effective and safe treatments are available^17,18. Society’s taboos, cultural background and misconceptions, etc. aggravate this situation. Hence, there is a medical need to provide reliable information on vaginal atrophy issues¹⁷.

The clinical picture, general menopausal signs, and gynecological examination are essential for diagnosis. The genitourinary syndrome may include, but is not necessarily limited to, genital symptoms of dryness, burning and irritation, sexual symptoms such as insufficient lubrication, pain during sexual intercourse (dyspareunia), urinary symptoms and recurrent urinary infections^2,10,14. Such atrophic effects usually become clinically apparent 4–5 years after the menopause, and vaginal atrophy is present in 25–50% of all postmenopausal women¹.

Objective findings of vaginal atrophy include reduced epithelial thickness, epithelial pallor, shortening of the vagina, reduced elasticity of vaginal walls, reduction of the vaginal diameter, reduction of pubic hair, shrinkage of the labia, increased vaginal pH up to 6–7, and loss of vaginal mucosal folds (rugae)^2,10,14. The main symptoms are vaginal dryness (estimated at 75%), dyspareunia, vaginal itching as well as vaginal discharge and soreness^2,10,14. Moreover, female urethral function may also deteriorate and urinary symptoms, such as incontinence and frequent urinary tract infections, are commonly observed^1,14.

Although VVA is typically a clinical diagnosis, laboratory tests may support the findings. Low vaginal epithelium maturation, atrophic smears with or without inflammation, a vaginal pH of more than 5.0 and decreased serum estrogen levels confirm the diagnosis. A decreased vaginal maturation index (VMI) or value describes the cytological changes in vaginal smears as a shift from superficial squamous cells towards intermediate epithelial cells¹⁹. In healthy women, VMI is within the 50–64% range and shows moderate estrogenic stimulation whilst a VMI value below 49% is indicative of vaginal atrophy^10,19. However, no consensus on optimal VMI calculation has been reached to date¹⁹.

Impact on quality of life

Estrogen loss affects different sexual domains leading to a negative impact on quality of life which is especially problematic for women who want to stay sexually active^14,20. Typical problems are significant increase in vaginal dryness, decrease in sexual desire, arousal, orgasm and dyspareunia¹⁷. The loss of sexual function leads to a redefinition of the feminine role of women as it affects all domains of quality of life, like self-esteem, including their social life and relationship with their partner^17,21.

Treatment with the combination of estriol and lactobacilli

Treatment principles

Vaginal atrophy is a progressive condition, but a positive vaginal response to therapy is rapid and sustained²². The IMS recommends using an ultra-low dose of vaginal estrogen, although long-term safety clinical data (more than 1 year) are still limited^1,23. A consensus on menopausal hormone therapy (MHT) stresses that local, low-dose estrogen therapy should be preferred in women with isolated vaginal dryness and/or associated dyspareunia²⁴. The recommendation is to administer the lowest local dose estrogen therapy in case long-term treatment is required^1,23. There is no documented evidence of clinically relevant endometrial effects if ultra-low-dose vaginal estrogen, especially E3, therapy is used. Nevertheless, before initiating the therapy, it is recommended to exclude endometrial pathology. Furthermore, other guidelines by scientific societies such as NAMS, The National Institute for Health and Care Excellence, the European Menopause and Andropause Society, and German S3 are in line with the aforementioned approach^25–29.

Non-hormonal substances

If hormones are unsuitable, vaginal lubricants or moisturizers could provide improved lubrication. It has been reported that oral phytoestrogens do not alleviate menopausal symptoms in breast cancer patients³⁰. In general, non-hormonal substances could provide temporary symptom relief but their long-term efficacy is very limited^1,23,28.

DHEA and SERMs

Promising, novel menopause therapies such as dehydroepiandrosterone (DHEA) and selective estrogen receptor modulators (SERMs) are currently recommended by the IMS for the treatment of VVA/GSM²³. Topical use of DHEA is promising in the treatment of VVA, especially in the case of associated sexual symptoms in women with contraindications to estrogens²³. Ospemifene, a novel SERM, is indicated for the systemic oral treatment of dyspareunia associated with VVA in women who are unable to take vaginal estrogens^23,31.

Estrogens

Due to the high concentration of estrogen receptors (ER – both ERα and ERβ) in the vulva and vagina as well as in the pelvic floor and urethral muscles, the bladder trigon is highly sensitive to estrogen deprivation^32,33. Hence, vaginal atrophy can effectively be treated with estrogens, including locally applied estrogens^1,34. Few studies have shown a correlation between the use of vaginal estrogens and a stimulating effect on the endometrium (development of endometrial atypical hyperplasia). However, only continuous vaginal use of high doses of ‘potent’ estrogens (like estradiol, E2) may have safety concerns as this effect is known to depend on hormone type, dose and frequency of administration³⁵.

Vaginally administered estrogens are absorbed in a dose-dependent manner^36,37. Vaginal estrogens are more effective in relieving urogenital symptoms than oral preparations because lower doses are required due to the absence of hepatic metabolism and high local estrogen concentrations^35,38. The use of local estrogen is the option of choice – it provides an effective and safe treatment that improves symptoms and restores women’s quality of life²⁰. In severe cases, women receiving systemic hormone therapy may require an additional vaginal estrogen as systemic therapy alone relieves vaginal atrophy symptoms in only about 75% of women³⁹.

Estriol

Estriol (E3) is a human-specific sex hormone. In addition to E3, two other estrogen hormones, namely estradiol (E2) and estrone (E1), are naturally present in humans³⁵. Whereas E2 and E1 can be reversibly metabolized into each other, E3 is a final metabolite of estrogen synthesis^40,41. E3 has been defined as a short-acting estrogen, since it has the shortest receptor occupancy and lowest receptor affinity of all estrogens – about 10 times weaker than E2³⁵. Thus, some estrogenic effects, so-called ‘early effects’, can be observed following single administration of E3, whereas ‘late effects’, which are based on a longer receptor retention time, are seen only with E2^40,42. In addition, rapid ER signaling seems to be important if E2 is used⁴³.

The endogenous daily production of E3 during the premenopause, calculated from the metabolic clearance rate and plasma concentration, is known to range around 14 ± 2 µg/day in the follicular phase and 23 ± 2 µg/day in the luteal phase. During the postmenopause, the mean value is 11 ± 4 µg/day^36,44–49. In serum, 8% of E3 is unbound and 92% is bound to transport proteins⁵⁰. The elimination half-life of E3 ranges from 9 to 10 h⁴⁷. More than 95% of E3 is eliminated via the urine in the form of glucuronides⁵⁰.

After oral administration, E3 is readily absorbed and metabolized in the liver, so that only 1–2% of the administered dose reach the circulation in an unchanged active form. Following administration of 8 mg of E3, a maximum serum level of 75–220 pg/ml is reached after 1–3 hours^36,50. Following vaginal application, about 20% of the dose reaches the circulation in an unchanged form. Correspondingly, similar systemic effects are produced by vaginal treatment compared to oral therapy with a 10–20-fold higher dose^40,50. Vaginal absorption of estrogen depends on the maturation status of the epithelium: E3 absorption via a well-proliferated vaginal epithelium is markedly lower than that via an atrophic one^47,51–53. Various authors have also concluded that repeated intravaginal administration of E3 leads to a slight cumulative effect^37,47. However, doses as high as 0.5 mg E3 twice weekly are not associated with a significant increase in serum estrogen levels after short- (weeks) and long-term (12 months) treatments⁵⁴.

After single-dose, oral or vaginal applications of E3 in conventional doses (oral: ≤ 8–10 mg; vaginal: ≤ 0.5 mg), there is no or only a weak proliferative effect on the endometrium^41,42. The lack of or weak stimulation of the endometrium by E3 can be explained by its pharmacokinetic and pharmacodynamic properties⁴¹. The mechanism of action in the vagina and uterus is similar with E3 and E2⁵⁵ but differs in terms of a 10-fold lower affinity of the ER for E3 versus E2^33,55.

Like all estrogens, E3 stimulates the proliferation and maturation of the vaginal epithelium but no clear differences in E3 receptor affinity have been found between the vagina and the endometrium^35,55. The comprehensive review of clinical studies investigating E3 has shown that intravaginal E3 appears to be effective in controlling local symptoms of menopause with a vaginal dose of 0.5 mg E3³⁵. A meta-analysis of all published studies concluded that once-daily treatment with intravaginal E3 (0.5 mg) is safe and has no increased risk of endometrial proliferation or hyperplasia⁵⁶.

Ultra-low-dose vaginal estriol (0.03 mg E3) has a beneficial efficacy-safety profile^{1,34,49,47,57–62}: (1) it displays similar efficacy to that of conventional dose (0.5 mg) preparations; (2) it does not increase systemic E2 and/or E1 levels, while its influence on systemic E3 levels depends on the dose and maturation status of the epithelium; (3) it shows no relevant influence on systemic levels of sex hormones; (4) it does not cause endometrial proliferation after 6 months of use and, accordingly, there is no need to use opposing progestogen; and finally, (5) no systemic adverse events are expected due to negligible absorption. Hence, as mentioned, topical administration of low-dose E3 is generally preferred³⁵.

Lactobacilli

For over a century, lactobacillary flora has been believed to maintain vaginal homeostasis, and any imbalance has potentially been associated with poor gynecological health outcomes.

Only probiotic Lactobacillus strains exhibit beneficial properties⁶³. Beneficial lactobacilli inhibit the growth of pathogens by producing various antimicrobial substances⁶³. In vitro experiments with L. acidophilus have demonstrated that the strain is able to produce substantial amounts of lactic acid⁶⁴. Another important defense mechanism^12,63,65 of beneficial lactobacilli strains involves the production of H₂O₂. Additional defense mechanisms such as the production of bacteriocins and biosurfactants, co-aggregation and lactobacilli biofilm formation have also been described⁸. Furthermore, beneficial lactobacilli strains compete with pathogens for adherence to the vaginal epithelium and for nutrients^63,66. Probiotics also show immune-modulating properties^7,63 – vaginal lactobacilli properly calibrate genital immune system responses via specific signaling processes^67,68.

Postmenopausal women with diminished estrogen levels have quite different vaginal flora compared to premenopausal women. The abundance of lactobacilli is substantially decreased, and women with vaginal atrophy display increased vaginal bacterial diversity^59,69,70. The estrogen therapy of VVA in postmenopausal women results in a vaginal epithelium resembling the premenopausal period⁵⁹ and beneficial lactobacilli flora are important for preventing vaginal infections. Concomitant treatment with probiotic lactobacilli is therefore considered as adjuvant therapy to restore the beneficial lactobacilli flora in these postmenopausal women⁴. The efficacy of exogenous lactobacilli for the restoration of the vaginal flora in premenopausal women having received anti-infective therapy is well documented^66,71. Furthermore, evidence of the synergistic effect of combined estriol–lactobacilli treatment in postmenopausal women has been shown in a clinical study investigating the improvement of urogenital aging⁵⁹.

Ultra-low-dose estriol and lactobacilli combination

A combination containing a very low dose of E3 (0.03 mg) and lyophilized, 100 million cfu (colony forming units) viable Lactobacillus acidophilus KS400 per vaginal tablet (0.03 mg-E3/L) has also been used in clinical studies to treat VVA and is approved in many countries. Its dual mechanism of action has been used for many years for conditions where the establishment and maintenance of a healthy vaginal ecosystem is important (Figure 1)⁶⁶, such as restoration of the vaginal flora, treatment of vaginal discharge and treatment of symptomatic vaginal atrophy in postmenopausal women. The dosage and duration of the estriol and lactobacilli combination depend on the clinical situation. The general rule in the treatment of vaginal atrophy is a single daily application for 12 days as initial therapy followed by a maintenance regimen of two to three doses per week⁶⁶.

Figure 1. Dual mechanism of action of 0.03 mg estriol/Lactobacillus acidophilus (0.03 mg-E3/L) combination^5,7,66.

The dose of E3 in 0.03 mg-E3/L combination therapy is substantially lower than that of conventional preparations. As stated earlier, topical E3 as the final metabolite of estrogen synthesis (Figure 2) is preferred for vaginal use in that it generates a sufficient local response without having a relevant effect on the endometrium¹.

Figure 2. Transformation of various estrogen types^40,41.

The Lactobacillus acidophilus KS400 strain contained in 0.03 mg-E3/L is of human origin and has been shown to possess the essential, beneficial in vitro properties for vaginal use⁶⁶.

In a pharmacokinetic study, Kaiser and colleagues⁷² demonstrated that basal plasma concentrations of unconjugated E3 during the 12-day treatment regimen with 0.03 mg-E3/L combination remained at the same level, indicating that no accumulation of E3 had taken place and that systemic effects were therefore unlikely. In contrast to the standard dose of 0.5 mg E3, 0.03 mg-E3/L combination neither produces significant absorption nor triggers a relevant increase in systemic E3 levels. Thus it is predominantly effective in the vagina with negligible systemic action⁷³. Another pharmacokinetic clinical study carried out by Donders and colleagues⁵³ in postmenopausal breast cancer survivors on aromatase inhibitors – the population with the lowest possible estrogen serum levels – suffering from severe symptomatic vaginal atrophy, clearly demonstrated that single vaginal application of 0.03 mg-E3/L generates only a small and transient rise in serum E3 levels (up to 44 pg/ml) in 50% of women at the start of treatment. However, serum levels of other sex hormones and binding proteins are not influenced at all. After repeated daily intravaginal application of the combination, E3 absorption could no longer be detected, presumably because of increased local metabolism by the matured epithelial maturation. Consequently, this treatment can be evaluated as being safe without any relevant risk of endometrial or other systemic effects and may be considered for breast cancer survivors on aromatase inhibitors^53,74.

Interestingly, combining E3 with lactobacilli has demonstrated synergistic effects⁵⁹. A clinical study by Capobianco and colleagues⁵⁹ demonstrated that 0.03 mg-E3/L combination was considerably more effective in reducing urogenital atrophy, the frequency of urinary tract infections and stress urinary incontinence compared to a 1 mg-E3 mono-preparation. The authors recommended this combination therapy as first-line treatment for urogenital aging in postmenopausal women⁵⁹.

Overall, the clinical efficacy of 0.03 mg-E3/L combination in the treatment of vaginal atrophy has been demonstrated in various clinical studies (Table 1)^{16,53,59,61,72,73,75–77}. More than 600 women have been evaluated. Clinical data revealed that vaginal 0.03 mg-E3/L leads to similar efficacy compared to the 16-fold higher dose of 0.5 mg⁷³. Furthermore, the equivalent efficacy of ultra-low-dose E3 in the treatment of vaginal atrophy has been also demonstrated in clinical studies using E3 mono-preparations^57,58,60. Recent clinical studies have highlighted the considerable efficacy of 0.03 mg-E3/L combination in treatment of VVA/GSM in various ways. Both initial (daily vaginal application for 2 weeks) and maintenance (two or three vaginal tablets weekly) therapeutic regimens have been studied and proved to be effective in treating and preventing the relapse of vaginal atrophy^{53,59,61,75,76}. Relevant improvements in signs and symptoms such as vaginal dryness, soreness and dyspareunia, in affected women have been demonstrated compared to placebo⁶¹ and comparators⁵⁹. In a pivotal study, Jaisamrarn and colleagues⁶¹ demonstrated the superiority of 0.03 mg-E3/L combination over placebo, with a significantly higher increase in VMI. During initial treatment, VMI increased considerably from the start of treatment to the first follow-up (after 2 weeks of initial therapy) and remained within the normal estrogenization range (> 50%) during 2 months of maintenance therapy^53,61. Interestingly, maximum E3 levels were inversely correlated with VMI values, demonstrating that the maturing epithelium rapidly precludes further E3 absorption after initial therapy⁵³. Additional flora parameters have also demonstrated positive dynamics in a consistent manner^61,76. The lactobacillary grade permanently improved from onset through to the end of initial therapy, and even during maintenance therapy^53,61. In addition, the improvement in signs and symptoms was accompanied by positive effects on sexual and overall quality of life⁷⁵.

Table 1. Overview of main publications with 0.03 mg estriol (E3)–Lactobacillus acidophilus KS400 combination (0.03 mg-E3/L) relating to the treatment of vaginal atrophy.

Publication	Design	Patients	Intervention	Outcome
Kaiser et al. 2000^72	Pharmacokinetic, open, monocentric, multiple-dose	8 menopausal volunteers aged 57–65	0.03 mg-E3/L, 1 tablet per day for 12 days	VMI improved substantially, plasma concentrations of E3 remained at same level, no accumulation
Kanne & Jenny, 1991^16	Double-blind, active- and placebo-controlled, randomized, parallel-group, dose-finding	15 women with atrophic vaginitis aged 51–65	0.03 mg-E3/L, 2 tablets per day for 6 days or E3 0.5 mg + lactobacilli or lactobacilli	No significant difference between test medication (0.03 mg E3) and active control (0.5 mg E3)
Feiks & Grünberger, 1991^73	Double-blind, randomized, active-controlled, parallel groups	48 women with atrophic vaginitis aged 49–69	0.03 mg-E3/L, 1 tablet per day for 12 days and E3 0.5 mg 1 ovule per day for 12 days	No significant difference between 0.03 mg-E3/L and 0.5 mg E3
Jaisamrarn et al. 2013^61	Double-blind, randomized, placebo-controlled, parallel groups	83 women with symptomatic vaginal atrophy	0.03 mg-E3/L, 1 tablet per day for 12 days +12 weeks’ maintenance therapy 1 tablet twice a week	Significant improvement or disappearance of clinical signs and symptoms, normalization of VMI and LBG compared to placebo. Only a few local adverse reactions
Donders et al. 2014^53	Pharmacokinetic, open, monocentric, multiple-dose	16 BC survivors under AI therapy suffering from severe symptomatic vaginal atrophy	0.03 mg-E3/L, 1 tablet daily for 28 days + maintenance therapy of 3 tablets weekly for 8 weeks	Serum E3 transiently increased after first application. After 4 weeks, serum E3 levels increased in only 50% of women. The product was well tolerated
Buchholz et al. 2015^75	Pharmacokinetic, open, monocentric, multiple-dose	16 BC survivors under AI therapy suffering from severe symptomatic vaginal atrophy	0.03 mg-E3/L, 1 tablet daily for 28 days + maintenance therapy of 3 tablets weekly for 8 weeks	Vaginal atrophy resolved or improved. All vaginal flora markers of vaginal microflora and epithelial vaginal cell quality improved dramatically
Donders et al. 2015^76	Pharmacokinetic, open, monocentric, multiple-dose	16 BC survivors under AI therapy suffering from severe symptomatic vaginal atrophy	0.03 mg-E3/L, 1 tablet daily for 28 days + maintenance therapy of 3 tablets weekly for 8 weeks	Sexually active increased from 19% to 63% (44% intercourse). The sexual questionnaire highlighted trend for improved sexuality parameters
Capobianco et al. 2014^59	Prospective randomized, parallel groups	136 postmenopausal women with urogenital aging	Group I: triple therapy 0.03 mg-E3/L per day for 2 weeks and two ovules once a week for 6 months + pelvic rehabilitation; Group II: one intravaginal estriol 1.0 mg ovule similar regimen + pelvic rehabilitation	Symptoms and signs of urogenital atrophy improved in both groups. Therapy with 0.03 mg-E3/L was more effective for urogenital aging in postmenopausal women due to synergic action

AI, aromatase inhibitor; BC, breast cancer; LBG, lactobacillary grade; VMI, vaginal epithelium maturation index.

Safety of ultra-low-dose estriol combined with lactobacilli

The safety of 0.03 mg-E3/L combination has been evaluated in more than 4000 women in various clinical studies, and only 1.7% adverse drug reactions were observed. Most of the side-effects (> 80%) were local reactions⁶⁶. There was no evidence of typical side-effects of systemic estrogen treatment such as thromboembolic events, in women who were taking 0.03 mg-E3/L vaginal tablets^1,66. Moreover, probiotic lactobacilli are known to be very well tolerated⁷⁸.

Panay and Fenton⁷⁹ clarified the confusion surrounding key safety issues relating to the use of local vaginal estrogen therapy: (1) concomitant progestogen application is not required because ultra-low-dose estrogens are unlikely to stimulate the endometrium; (2) the overall duration of treatment is usually not limited; and (3) the use of vaginal estrogens is often necessary even during systemic hormone therapy.

Conclusions

In conclusion, the use of ultra-low-dose 0.03 mg E3 in combination with lactobacilli (0.03 mg-E3/L) for the treatment of VVA/GSM represents a modern medical concept. Both sufficient estrogen levels and colonization by lactobacilli are essential to restore and maintain a healthy vaginal ecosystem. An ultra-low-dosed E3, with no risk of endometrial proliferation, stimulates the vaginal epithelium and supports the development of physiological flora. Probiotic lactobacilli work through a variety of mechanisms to reinstate homeostasis by commensal colonization, blocking adhesion of pathogens, enhancing epithelial barrier function and influencing antimicrobial peptide secretion and the mucosal immunity of the human vagina. Hence, the 0.03 mg-E3/L combination displays synergistic action and considerably improves the clinical signs and symptoms as well as the quality of life of women suffering from vaginal atrophy. This combination therapy is well tolerated with a low overall incidence of side-effects and negligible E3 absorption. Based on recent scientific evidence and current treatment guidelines, 0.03 mg-E3/L combination could be considered one of the options for the treatment of symptomatic vaginal atrophy in aging menopausal women.

Conflict of interest

Dr Philipp Grob and Dr Valdas Prasauskas are employees of Medinova AG, Switzerland. Other authors over the past 2 years have had no conflict of interest in relation to this publication. The authors are solely responsible for the content and writing of the paper.

Acknowledgements

The authors would like to thank Gabriela Zwyssig, Medinova AG, Switzerland, and Dr Christian Rosé, Pierre Fabre, Germany, for their comments on the manuscript.

Additional information

Funding

The preparation of this review and online open access of the publication were sponsored by Medinova AG, Switzerland.