Gynecological Endocrinology

ISSN: 0951-3590 (Print) 1473-0766 (Online) Journal homepage: https://www.tandfonline.com/loi/igye20

Local ultra-low-dose estriol gel treatment of vulvo-

vaginal atrophy: efficacy and safety of long-term
treatment

Paola Villa, Valeria Tagliaferri, Inbal Dona Amar, Clelia Cipolla, Fabio
Ingravalle, Giovanni Scambia, Walter Ricciardi & Antonio Lanzone

To cite this article: Paola Villa, Valeria Tagliaferri, Inbal Dona Amar, Clelia Cipolla, Fabio
Ingravalle, Giovanni Scambia, Walter Ricciardi & Antonio Lanzone (2019): Local ultra-low-
dose estriol gel treatment of vulvo-vaginal atrophy: efficacy and safety of long-term treatment,
Gynecological Endocrinology, DOI: 10.1080/09513590.2019.1702016

To link to this article: https://doi.org/10.1080/09513590.2019.1702016

Published online: 17 Dec 2019.

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GYNECOLOGICAL ENDOCRINOLOGY
https://doi.org/10.1080/09513590.2019.1702016

ORIGINAL ARTICLE

Local ultra-low-dose estriol gel treatment of vulvo-vaginal atrophy: efficacy and

safety of long-term treatment
Paola Villaa,b, Valeria Tagliaferria,c, Inbal Dona Amara,b, Clelia Cipollaa,b, Fabio Ingravalled, Giovanni Scambiaa,b,
Walter Ricciardia,b and Antonio Lanzonea,b
a
Department of Woman, Child and Public Health, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Roma, Italy; bUniversita Cattolica del
Sacro Cuore Sede di Roma, Roma, Italy; cDepartment of Obstetrics and Gynaecology, Ente Ecclesiastico Ospedale Generale Regionale Francesco
Miulli, Acquaviva delle Fonti, Italy; dDepartment of Biomedicine and Prevention, Universita degli Studi di Roma Tor Vergata Facolta di Medicina
e Chirurgia, Roma, Italy

ABSTRACT ARTICLE HISTORY

Vulvo-vaginal atrophy (VVA) is a chronic condition affecting many postmenopausal women. Local estro- Received 26 August 2019
gen treatment is recommended. Evaluating efficacy and safety of long-term VVA treatment with ultra- Revised 17 September 2019
low-dose estriol gel, 120 postmenopausal VVA women were enrolled in a prospective study. They Accepted 4 December 2019
received the first cycle of 1 g/day vaginal gel containing 50 mg estriol for 3 weeks and then twice a week Published online 17 Decem-
ber 2019
for 12 weeks. Moderate or severe VVA women received a second treatment cycle reaching treatment of
30 weeks. Vaginal pH measurement, subjective symptoms, and objective signs assessment of VVA, endo- KEYWORDS
metrial thickness and adverse events (AE) were recorded. Of the 99 women, completing the first phase, Vaginal atrophy;
43% experienced a complete VVA symptom relief, and 65% presented a milder VVA degree. After menopause; estriol; quality
30 weeks, VVA signs significantly improved (p<.01) compared with baseline and first phase results; total of life; vaginal dryness
objective symptom evaluation including Schiller’s test, flattening of folds and vaginal pH significantly
improved (p<.01). At study endpoint, none of the patients had severe VVA, 93% had a positive response,
75% had a complete symptom, and sign resolution. No treatment-related endometrial AE were observed.
Postmenopausal VVA long term-treatment with ultra-low-dose estriol vaginal gel is safe and effective.

Introduction are distressed by symptoms without estrogen intervention [6].

Few clinical trials have been focused on the safety LET profile
Many menopausal women experience vulvo-vaginal atrophy
after 12 months. Contrariwise, it is well known that urogenital
(VVA), a common condition associated with estrogen level
symptoms of postmenopausal women often require long-term
depletion. This condition that remains often neglected and
therapy since women reported the return of symptoms during
untreated, affects about 79% of all postmenopausal women [1,2]
wash-out periods between different treatments [13].
and is characterized by vaginal tissue thinning and shrinking,
We conducted a prospective trial to evaluate the effectiveness
decreased vaginal wall lubrication, rugae loss, and vagina short-
and safety of a long-term ultra-low-dose estriol gel treatment
ening/narrowing related to elasticity and distensibility loss.
(GelistrolV vaginal gel 1 g containing 50 mcg of estriol) and the
R

Women may suffer from dyspareunia, vaginal burning, itching,

and other bothersome symptoms that may negatively affect sex-
ual health and quality of life [3,4]. Circulating estrogen decline is
considered the main VVA cause [5]. Hormonal therapy (HT) is
often requested after non-hormonal intervention failure such as
vaginal lubricants and moisturizers. According to The North
American Menopause Society (NAMS) guidelines [6], local estro-
gen therapy (LET) provided great benefits especially if vaginal
symptoms were the only patient complaint. LET improved VVA
associated symptoms, with a low-risk profile linked to limited
systemic absorption and reduced adverse effects (AE) occurrence
[7,8]. LET demonstrated effectiveness and women satisfaction
resulting in a 90% symptom relief compared with oral estrogen
therapy demonstrating 75% relief [9,10]. Health authorities and
menopause societies recommend prescribing the lowest effective
estrogen doses to balance treatment goals and risks for VVA
women [6,11,12].
LET duration in VVA women is an ongoing concern. NAMS
2013 position statement supports the LET use as long as women
patient medication-adherence.
Materials and methods
From 2015 until 2018, a total of 120 women attending the
Outpatient Menopause Service of our hospital were enrolled in
this prospective study. The study protocol was approved by the
Institutional Review Board (nr.2.12/6/2014). Each participant
signed written informed consent and the study was conducted in
accordance with the Declaration of Helsinki. Inclusion criteria
were postmenopausal women aged between 40 and 75 years with
at least 12 months of amenorrhea and clinical VVA diagnosis.
VVA documentation included symptoms description and sexual
history. The coexistence of three parameters was required to
diagnose VVA:
1. Subjective perception of vaginal dryness (of any intensity);
2. Vaginal pH >5;

CONTACT Paola Villa paola.villa@policlinicogemelli.it Department of Woman, Child and Public Health, Policlinico Universitario Agostino Gemelli, Roma, Italy
ß 2019 Informa UK Limited, trading as Taylor & Francis Group
2 P. VILLA ET AL.

Table 1. Demographic and clinical characteristics of the patients at baseline. gynecologist performed TV-ultrasound to evaluate endometrial
Baseline characteristics Study group (n ¼ 120) thickness at baseline and during the two follow up visits. AE,
Age at enrollment 57.4 ± 8.3 endometrial thickness, vaginal and/or urinary infections, and
Age at menopause 47.8 ± 5.4 treatment compliance were evaluated during three all visits.
Surgically induced menopause, % 15%
BMI 24.1 ± 2.8
Parity, % Statistical analysis
Nulliparous 9.2%
One or more children 91.8% Data are expressed as mean and standard deviation or as per-
Current smokers 8% centage. Difference between means of the two groups was calcu-
Subjective evaluation Study group (n ¼ 120) lated with the 2-tailed t-test for independent samples. The
Vaginal dryness (score 0–10) 8.3 ± 1.4 Bonferroni test was performed to analyze data. A p < .05 was
Dyspareunia (score 0–10) 8.2 ± 1.7 accepted as significance threshold, other reported significance
Itching (score 0–10) 2.3 ± 2.1 values were p<.01 and p<.001. All analysis was performed using
Burning (score 0–10) 3 ± 2.2
Dysuria (score 0–10) 1.9 ± 1.2
R version 3.4.2 and R-Studio version 1.1.383.
TS-VAS 8.4 ± 1.4
Objective evaluation Study group (n ¼ 120) Results
Schiller’s test (score 1–3) 1.9 ± 0.9
Table 1 presents baseline patient characteristics. Mean age at
Flattening of folds (score 1–3) 1.8 ± 0.5
Pallor of the mucosa (score 1–3) 2 ± 0.6 menopause was 47.8 ± 5.4 years.
Presence of petechiae (score 1–3) 2.3 ± 0.7 The most common and bothersome symptoms reported by
pH (score 1–3) 1.2 ± 0.2 VAS scale were vaginal dryness and dyspareunia.
TO-Score 8.7 ± 1.8 Among 120 women enrolled, 99 completed the first phase of
Severity of symptoms at the objective evaluation Study group (n ¼ 120) the study treatment and 56 patients continued therapy. Figure 1
Mild 9.5% represents the study flow chart. Twenty-one patients withdrew
Moderate 62% from the study.
Severe 28.5% At primary objective evaluation, 9.5% of women suffered
mild, 62% moderate, and 28.5% severe VVA. Forty-three of 99
patients, who completed the first study phase, experienced com-
3. One objective VVA sign (either vaginal mucosa with flatten- plete symptom relief and completed the study, and 56 were
ing of folds or thinned, pale, fragile mucosa with petechiae). addressed to a second treatment cycle, because VVA was still
A body mass index (BMI)
28, endometrial thickness
4 mm classified as moderate or severe. Two of 56 patients were lost to
measured before the study initiation by transvaginal (TV) ultra- follow-up.
sound, and/or abnormal vaginal bleeding, hormone-dependent Figure 2 highlights the subjective perception (panel A) and
malignant lesion history, thromboembolic disease, and liver dis- the objective evaluation (panel B) basally, after the first and the
ease were considered exclusion criteria. We excluded women second study phase.
treated for VVA up-to 3 months before the study beginning. We observed after 30 weeks of therapy significant improve-
Subjective symptoms were scored in a 0–10 visual analog ment of vaginal dryness, dyspareunia, and burning (p<.05) com-
scale (VAS) (with 0 ¼ total symptom absence and 10 ¼ worst pared with baseline and first cycle data. The TS-VAS reported by
symptoms). An individual overall and subjective VVA perception women resulted to be significantly improved (p<.01) compared
was recorded using the 0–10 VAS scale (total subjective VAS, with baseline.
TS-VAS). Regarding the objective evaluation, a significant improvement
The objective evaluation included Schiller’s test (with of the Schiller’s test (p<.05), flattening of folds (p<.01), and PH
1 ¼ negative; 2 ¼ slight; 3 ¼ positive). Evaluation of clinical fea- reduction after 30 weeks of treatment compared with baseline
tures (flattening of folds, paleness, and petechiae) was performed (p<.01) were documented. Comparing the first and second treat-
according to intensity (from 1 ¼ maximum to 3 ¼ null). PH was ment cycles, further clinical improvements emerged: vaginal folds
scored (1 ¼ pH >5.5; 2 ¼ pH 5.4–4.5; 3 ¼ pH <4.5) with a higher increase, petechiae, and PH significant decrease (p<.01). The
value corresponding to improved clinical features. The sum of TO-Score resulted significantly higher comparing baseline and
these parameters resulted in a final total objective score, i.e. TO- first cycle (p<.01). At the end of the long-term treatment, none
Score. The higher the TO-Score, the more improved the object- of the patients had severe VVA; 33% had mild and 3.7% moder-
ive overall signs. ate VVA; 63% showed a completely resolved condition.
Based on TO-Score, we established three VVA degrees: mild Considering the subjective perception, 93% of patients had a
(TO-Score
12); moderate (TO-Score ranging from 10 to 12); positive response and 75% had a complete resolution.
severe (TO-Score <10). TO-Score >15 indicates absence No treatment-related endometrial AE were observed.
of VVA. At baseline the mean endometrial thickness was 3.5 ± 0.4 mm,
During the first study phase (15 weeks), each woman received at 4 months 3.3 ± 0.6 mm and at treatment end 3.4 ± 0.4 mm.
1 g of vaginal gel containing 50 lg of estriol (GelistrolV,
R
Four patients had vaginal infection during the first phase of
Italfarmaco, Milano, Italy) daily for 3 weeks and twice weekly for the study and one patient during the second phase causing study
12 weeks. Subsequently, patients with moderate or severe VVA, discontinuation. No other AE were noted.
according to TO-Score, were addressed to a similar second treat-
ment cycle for 15 weeks. Patients with mild to absent VVA (TO- Discussion
Score
12) discontinued the treatment.
Examinations were performed at enrollment (baseline), after Our longitudinal study including subjective and objective outcome
15 weeks and after further 15 week-treatment. The same measures, confirmed the efficacy of ultralow dose therapy seen in

Figure 1. Flow chart of the patients through the study.
previous studies [13–17] and first, showed that long-term treat-
ment further increases the benefits in low responsive patients
[18,19]. No treatment-related endometrial AE were observed.
Study data evidenced that after the long-term treatment cycle
(>7 months), 93% of patients responded positively, 75% had a
complete resolution of subjective symptoms, and 63% of object-
ive parameters. After the first treatment cycle, 65% of patients
presented a milder VVA degree while 43% of patients experi-
enced complete relief. Regarding each symptom, a significant
improvement of vaginal dryness, dyspareunia, and dysuria was
observed after both study phases.
Objective tools including vaginal folds appearance, PH, and
TO-score, confirmed the patients’ subjective reports regarding
the beneficial effects of the treatment.
This demonstrates that ultra-low-dose estrogen is efficient in
lowering VVA’s most bothersome symptoms and an initial
improvement is achieved even after a short treatment cycle.
At study endpoint, VVA signs and symptoms further
improved compared with baseline and first phase results and
none of the patients presented severe VVA.
These findings indicate that with treatment prolongation fur-
ther improvement in VVA to the extent of complete symptoms’
resolution was noted.
GYNECOLOGICAL ENDOCRINOLOGY 3
Recent literature indicates that vaginal response to LET in
women affected by VVA is effective in a short period [14].
However, the real open question is ‘what is the best dosage
and treatment duration that guarantee a good risk/benefit ratio’?
Menopausal VVA is a chronic condition; estrogen deficiency-
related urogenital symptoms may require long-term therapy.
Currently, few long-term studies evaluated the safety profile.
Although barriers to long term LET use still exist our study
shows the absence of AE.
The efficacy and the grade of response to treatment depend on
the atrophy’s severity at treatment initiation. In our study, most of
the patients that started therapy with moderate atrophy improved
after 15 weeks. Particularly, 31% of the patients improved from
moderate to mild VVA, while 22% passed from severe to moder-
ate. Interestingly, further improvement of VVA symptoms and
signs was shown with another cycle of ultra-low-dose LET.
To our knowledge, a previous open-label none randomized
study verified the effects of a vaginal estradiol ring and or estriol
cream long-term therapy (up to 1 year) [13]; our study is the
first showing the good performance of the ultra-low-dose LET.
As already demonstrated, when applied vaginally, estriol
serum levels increase 1 h after the application and progressively
return to baseline [20].
4 P. VILLA ET AL.
Figure 2. Subjective (panel A) and objective (panel B) evaluation of VVA at baseline (black bars), at 15 weeks (dark gray bars), and at 30 weeks (light gray bars).
Panel A: the lower the value, the more improved the relevant subjective symptom. Panel B: the higher the value the more improved the clinical feature. p<.05,
p<.01 vs. baseline; §p<.05, §§p<.01 vs. 15 weeks.
Collet et al. [21] performed a study having 6 months follow
up period. Neither evidence of elevated blood estriol nor
systemic effects on breast or endometrium was shown during
follow up.
Similarly, a recent review evidenced that, when administered
vaginally, estriol preparations appear to be safe, indicating no
increase in serum estriol for 6 months [20].
Our data can be considered relevant and provide reassurance
to women with VVA who may otherwise hesitate to accept a
hormonal form of treatment for long periods. Conversely,
patients’ adherence to treatment is imminent to fully realize
the benefits.
Regarding medication-adherence, the proportion of subjects
who discontinued the treatment was 17.5% during the first phase
and a further 10% in the second phase. Reasons for discontinu-
ation were the messy application, personal preference of different
preparations, cost, and perception of achieving the desired effect
only after few applications.
In conclusion, this study demonstrated the continuous effi-
cacy and safety of the local ultra-low-dose estriol therapy in a
long-term administration for the treatment of VVA from both a
subjective and objective point of view.
This should encourage clinicians to take an active role in the
evaluation of VVA suggesting that long-term treatments are
appropriate for treating VVA in postmenopausal women.
Disclosure statement
The authors declare no potential conflicts of interest.
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