A randomized, pilot trial comparing vaginal hyaluronic acid to vaginal estrogen for the treatment of genitourinary syndrome of menopause

Women who suffer from genitourinary syndrome of menopause were treated with either vaginal estrogen or vaginal hyaluronic acid, and both groups noted improvement in symptoms after 12 wk of treatment. Vaginal hyaluronic acid may be a promising non-hormonal therapy for genitourinary syndrome of menopause.

Abstract

Objective

The aim of this study was to compare the efficacy of a non-hormone alternative, vaginal hyaluronic acid (HLA), to a standard-of-care therapy, vaginal estrogen, for the treatment of genitourinary syndrome of menopause (GSM).

Methods

This was a randomized, parallel arm pilot trial. Women with GSM were randomized to an HLA vaginal suppository or vaginal estrogen cream for 12 wk to compare the primary outcome, the vulvovaginal symptom questionnaire (VSQ) score. Secondary outcomes included the following: the female sexual function index (FSFI), the vaginal symptom index (VSI), visual analog scale (VAS) for dyspareunia, vaginal itching, and vaginal dryness, patient global impression of improvement (PGI-I) at follow-up, vaginal maturation index, and vaginal pH. Differences between treatment groups were estimated using the two-sided, two-sample t-test and 95% confidence intervals.

Results

Forty-nine women were randomized and 45 participants (vaginal estrogen = 23, vaginal HLA = 22) provided data at week 12. Baseline characteristics were similar in both groups. On the VSQ, there was no observed difference in overall scores between the HLA and vaginal estrogen groups at 12 wk (P = 0.81). Improvement was seen within both treatment groups on the VSQ after 12 wk. The VAS score, total VSI score, total FSFI score, and vaginal pH improved over time; however, improvement did not differ between study arms. Over 90% participants noted improvement on the PGI-I in both groups (P = 0.61). No treatment-related serious adverse events occurred.

Conclusions

There were no clinically meaningful differences between vaginal HLA and vaginal estrogen for the treatment of GSM after 12 wk. Vaginal HLA may be a promising non-hormone therapy for GSM.

Genitourinary syndrome of menopause (GSM) includes a wide constellation of symptoms related to sexual, lower urinary tract, and vulvovaginal health.¹ Between 26% and 85% of postmenopausal women report symptoms of GSM with the most common symptoms being vaginal dryness, dyspareunia, and vaginal irritation or itching.²

Vaginal estrogen has been the mainstay of therapy for GSM and has been shown in several studies to improve objective and subjective GSM measures.³ Importantly, several studies have also shown that vaginal estrogen has an acceptable safety profile with the most common side effects being increased vaginal secretions and vaginal itching.⁴ Despite the robust evidence supporting the use of vaginal estrogen for GSM, there are barriers that limit its use.⁵

In the lay media, there is often misrepresentation regarding the safety data on vaginal estrogen. After publication of the Women's Health Initiative results from 2002 and the subsequent Food and Drug Administration's (FDA) black box warning on all estrogen products—regardless of vaginal versus oral formulation type—many women are fearful of using any kind of hormone therapy (HT).⁶

Even after women are educated that the risks of oral estrogen do not apply to the low-dose topical form, there are still some women who decline vaginal HT. Additionally, providers are often hesitant to prescribe vaginal estrogen to women with a history of breast cancer (if they are not on aromatase inhibitors) and/or a history of venous thromboembolism, despite evidence to suggest that vaginal estrogen in these sub-populations may also be safe.^7-9

To provide women and providers with a spectrum of options they feel comfortable with for GSM, exploring non-hormone therapies, like vaginal hyaluronic acid (HLA), are important. Only a few studies involving vaginal HLA have been completed thus far, and they have been small and mostly used internationally available formulations of HLA and estrogen.^10,11

The objective of this study was to compare the efficacy of a non-hormone alternative, vaginal HLA, to a standard-of-care HT, vaginal estrogen, for the treatment of GSM for 12 wk, measured by improvement in vulvovaginal symptoms.

METHODS

Study design

This was an institutional review board–approved, randomized, parallel arm trial published on clinicaltrials.gov (NCT04544475) comparing treatment efficacy of vaginal HLA to vaginal estrogen for GSM. Enrollment began September 2021, and the last follow-up visit occurred in August 2022.

Participant recruitment

Women were recruited from urogynecology and urology practices at New York University Langone's Center for Female Pelvic Medicine. Women who were postmenopausal as defined by amenorrhea for greater than 12 mo, history of bilateral salpingo-oophorectomy, or history of hysterectomy and menopausal symptoms for greater than 1 yr were included. Participants also needed to have symptoms consistent with a diagnosis of GSM and a history of Pap smear screening as per American Society of Colposcopy and Cervical Pathology guidelines, with the most recent Pap smear being negative if one was indicated.

Exclusion criteria included use of any HT (systemic or local) or aromatase inhibitors within 6 wk of proposed start date, any medical contraindication to estrogen-based therapy, undiagnosed vaginal bleeding in the past 12 mo, impaired mental status, prior pelvic irradiation, and active vaginal infection. Appointments were screened each day for potential eligible participants.

Randomization

The randomization scheme was computer-generated and was blocked every four allocations.

Participants were randomized in a one-to-one ratio to either the HLA vaginal insert or vaginal estrogen cream. Masking of participants was not possible in this study due the different formulations of the drugs (insert versus cream). After randomization, participants were either given 12 wk of HLA vaginal inserts or vaginal estrogen cream.

Study interventions

The HLA used in this study was an FDA-approved vaginal lubricant and moisturizer composed of 5 mg of HLA sodium salt and a base of semi-synthetic glycerides.¹² It was in the form of a vaginal insert and did not require an applicator. Participants were instructed to place the insert vaginally, while laying down, twice weekly for 12 wk.

The vaginal estrogen used in this study was an FDA-approved low-dose vaginal estradiol cream composed of 100 μg of estradiol per 1 g of cream.¹³ Participants were instructed to place 0.5 g of cream with the provided applicator vaginally twice a week for 12 wk. Although there are many dosing regimens and schedules for vaginal estrogen cream, we chose a common starting dosage and preferred to keep the frequency to twice weekly to ensure both arms of the study required the same level of medication effort.¹⁴ Participants were given a medication diary to record the dates they used their assigned medication.

Outcome measurement

The primary outcome was the overall score on the vulvovaginal symptom questionnaire (VSQ). The VSQ is a 21-question survey that specifically asks about GSM symptoms—their emotional impact, sexual impact, and life impact. It has been found to have reliability and internal consistency.¹⁵ In the absence of a gold standard instrument to assess the global quality of life impact of GSM, this questionnaire is a critical new tool that is nuanced and disease-specific. The overall score is calculated by summing all individual questions and a higher score indicates more symptom bother.

Secondary outcomes included both subjective and objective outcomes. Subjective outcomes included the following: VSQ sub-scores, female sexual function index (FSFI) scores, a modified vaginal symptom index (VSI) score, and the visual analog scale (VAS) for dyspareunia, vaginal itching, and vaginal dryness. The FSFI is a well-validated 19-question detailed survey on women's sexual health.¹⁶ The FSFI score is a weighted sum with a lower overall score indicating worse sexual function. The VSI captures the intensity of four common vulvovaginal symptoms from “none” (score 0) to “severe” (score 3), and we additionally asked about vaginal discharge due to that being a common complaint of vaginal estrogen users.¹⁷ The overall score is a simple sum with a higher score indicating more symptom bother. The VAS captures the intensity of common GSM symptoms from a graphical prompt. Participants were asked to place an X along a 10-cm line to indicate their symptom severity from “no symptoms” (score 0) to “intolerable symptoms” (score 10).¹⁸ Additionally, participants were asked to fill out the patient global impression of improvement (PGI-I) at the follow-up visit, with choices ranging from “very much better” (score 1) to “very much worse” (score 7).

For objective secondary outcomes, the following was obtained: vaginal pH and a vaginal cell sample for calculating the vaginal maturation index (VMI). The VMI is a marker of estrogen's effect on vaginal cell maturation from parabasal to intermediate to superficial cells.¹⁹ Cytopathologists, trained in analyzing vaginal cell samples, were given the specimens in a blinded fashion, so they were unaware of any participant details, including randomization assignments.

At the baseline visit, demographic and gynecologic history was obtained. Of note, patients were allowed to mark “other” for their race without further delineation. At the baseline and 12-wk follow-up visits, primary and secondary outcomes were obtained. At the 12-wk follow-up visit, participants were first asked to report any medication side effects or adverse reactions that they had not reported to the study team already. Their medication diary was reviewed and treatment compliance recorded (number of doses used/24 total doses).

Statistical analysis

Due to the pilot design of this study, a sample size calculation was not performed a priori. Because GSM is a symptom-driven disease and participants will likely adhere to a treatment plan if they perceive symptomatic improvement, the authors chose the primary endpoint to be the contrast between the overall VSQ score after 12 wk of treatment, adjusted for baseline, between randomized arms. Secondary endpoints included comparisons of the VSQ sub-scores, FSFI scores, VSI scores, the VAS scores, the vaginal pH, and the VMI at 12-wk follow-up between randomized arms, adjusted for baseline. Adjustment for baseline refers to subtracting the baseline value from the 12-wk value within each group.

Descriptive statistics characterized participants at study entry. An intention-to-treat approach of completers was utilized, in which all participants who completed week 12 were included in analyses of efficacy and included in the group into which they were randomized, without regard to treatment use. The average difference in outcomes between arms, adjusted for baseline (mean difference in the change from baseline between randomized groups), is estimated for continuous outcomes with the associated 95% confidence interval (CI); the two-sided, two-sample t-test, assuming unequal variance, is used to test the hypothesis of differences between arms. For categorical outcomes, such as the PGI-I, Fisher's exact test was used due to few participants in comparison groups. A two-sided P-value of less than 0.05 was considered statistically significant. Analyses were performed using SAS 9.4 (Cary, NC).

RESULTS

Fifty-six women were screened, 49 were determined to be eligible for the study, and 26 were randomized to vaginal estrogen and 23 to HLA (Fig. 1). Four individuals were lost to follow-up, three in the vaginal estrogen group and one in the vaginal HLA group.

FIG. 1.

Participant allocation.

Baseline characteristics were not clinically different across groups (Table 1). The average age was 60 yr old (vaginal estrogen IQR: 55 to 68; HLA IQR: 57 to 65), and the average number of years from menopause was 10 yr (vaginal estrogen IQR: 6 to 14; HLA IQR: 7 to 18) in both treatment arms. Overall, vaginal dryness was the predominant GSM symptom, followed by dyspareunia.

TABLE 1.

Participant characteristics

	Vaginal estrogen (n = 26)	Vaginal HLA (n = 23)
Age, median (IQR)	59.5 (55-68)	60 (57-65)
Education, % (n)
High school	7.7% (2)	13% (3)
Undergraduate	38.5% (10)	52.2% (12)
Masters	30.8% (8)	17.4% (4)
Doctorate	15.4% (4)	17.4% (4)
Other	7.7% (2)	0
Race, % (n)
Asian	3.8% (1)	8.7% (2)
Black	7.7% (2)	21.7% (5)
White	76.9% (20)	56.5% (13)
Othera	11.5% (3)	4.3% (1)
Not reported	0	8.7% (2)
Ethnic, % (n)
Hispanic or Latino	15.4% (4)	17.4% (4)
Not Hispanic or Latino	84.6% (22)	82.6% (19)
Marital status, % (n)
Single	23.1% (6)	56.5% (13)
Married	65.4% (17)	39.1% (9)
Partnered	3.8% (1)	4.3% (1)
Other	7.7% (2)	0
Current alcohol use, % (n)	53.8% (14)	60.9% (14)
Current smoker, % (n)	11.5% (3)	4.3% (1)
Total number of pregnancies, median (IQR)	2 (1-3)	2 (0-2)
Number of vaginal deliveries, median (IQR)	1 (0-2)	0 (0-2)
Number of years since menopause, median (IQR)	10 (6-14)	10 (7-18)
History of any hormone therapy use, % (n)	7.7% (2)	13% (3)
History of hysterectomy, % (n)	15.4% (4)	21.7% (5)
History of oophorectomy, % (n)	3.8% (1)	13% (3)
Current vaginal dryness, % (n)	96.2% (25)	100% (23)
Current vaginal burning, % (n)	38.5% (10)	43.5% (10)
Current dyspareunia, % (n)	73.1% (19)	78.3% (18)

HLA, hyaluronic acid; IQR, interquartile range.

^aIf a participant chose “other” for their race, they were not asked to further delineate their race.

For the primary outcome, overall VSQ score, a clinically meaningful difference between the HLA and vaginal estrogen groups at 12 wk, adjusted for baseline scores, was not observed (Table 2, mean difference between arms: −0.4; 95% CI, −3.5 to 2.8; P = 0.81). In all participants, sub-domains of the VSQ improved after 12 wk; however, these improvements did not differ substantially between treatment groups.

TABLE 2.

Primary and secondary outcomes by randomized treatment adjusted for baseline

	Vaginal estrogen		Vaginal HLA
	Baseline, mean (SD) (n = 26)	Mean change at 12 wk from baseline (95% CI) (n = 23)	Baseline, mean (SD) (n = 23)	Mean change at 12 wk from baseline (95% CI) (n = 22)	Mean difference between arms, adjusted for baselinea (95% CI)	Pb
Vulvovaginal symptom questionnaire score
Overallc	5.2 (5.2)	−3.7 (−6.0 to −1.3)	5.8 (4.7)	−3.3 (−5.5 to −1.1)	−0.4 (−3.5 to 2.8)	0.81
Symptoms domain	1.7 (1.7)	−0.7 (−1.4 to 0)	2.4 (2.1)	−1.1 (−2.2 to −0.1)	0.4 (−0.8 to 1.6)	0.50
Emotions domain	0.9 (1.3)	−0.7 (−1.3 to −0.1)	1.0 (1.3)	−0.6 (−1.3 to 0)	−0.06 (−0.9 to 0.8)	0.88
Life-impact domain	0.7 (1.5)	−0.8 (−1.5 to −0.1)	0.8 (1.3)	−0.7 (−1.3 to −0.1)	−0.1 (−1.0 to 0.8)	0.82
Sexual-impact domain	1.9 (1.8)	−1.4 (−2.3 to −0.5)	1.6 (1.7)	−0.8 (−1.6 to 0)	−0.6 (−1.8 to 0.6)	0.30
Visual analog scale scored
Dyspareunia	5.3 (3.6)	−3.6 (−5.1 to −2.1)	5.1 (3.4)	−3 (−4.4 to −1.5)	−0.6 (−2.6 to 1.4)	0.54
Vaginal itching	2.5 (2.8)	−0.8 (−2.6 to 1)	2.6 (2.8)	−1.6 (−3 to −0.3)	0.8 (−1.4 to 3.0)	0.45
Vaginal dryness	6.6 (2.3)	−4 (−5.6 to −2.5)	6.3 (2.5)	−3.4 (−4.7 to −2.1)	−0.7 (−2.6 to 1.3)	0.51
Vaginal symptom index score
Overalle	6.8 (3.7)	3.3 (1.4 to 5.3)	6 (3)	2.8 (1.2 to 4.4)	0.6 (−1.9 to 3.0)	0.64
Dryness	2.3 (0.9)	1.2 (0.6 to 1.7)	2 (0.9)	0.9 (0.4 to 1.3)	0.3 (−0.4 to 1.0)	0.38
Soreness	1.2 (1.2)	0.7 (0.1 to 1.3)	1.1 (0.9)	0.5 (0 to 1.1)	0.2 (−0.6 to 0.9)	0.70
Irritation	1.1 (1.1)	0.6 (0 to 1.2)	1.3 (0.9)	0.7 (0.2 to 1.2)	−0.1 (−0.9 to 1.3)	0.76
Discharge	0.2 (0.6)	−0.4 (−0.8 to −0.1)	0.2 (0.5)	−0.1 (−0.3 to 0.1)	−0.3 (−0.7 to 0.1)	0.13
Dyspareunia	2.1 (1.1)	1.3 (0.9 to 1.8)	1.5 (1.1)	0.8 (0.4 to 1.3)	0.5 (−0.1 to 1.1)	0.08
Female sexual function index score
Overallf	13.4 (8.8)	−9.1 (−12.2 to −6)	13.8 (8.6)	−5.3 (−8.1 to −2.5)	−3.9 (−7.9 to 0.2)	0.06
Desire	2.7 (1.1)	−0.5 (−0.8 to −0.2)	2.5 (1.1)	−0.5 (−0.8 to −0.1)	−0.01 (−0.4 to 0.4)	0.98
Arousal	2.4 (1.9)	−1.4 (−2 to −0.8)	2.4 (1.8)	−0.6 (−1.3 to 0.1)	−0.8 (−1.7 to 0.1)	0.09
Lubrication	1.6 (1.7)	−2.1 (−3 to −1.3)	1.9 (1.8)	−0.9 (−1.5 to −0.3)	−1.2 (−2.2 to −0.3)	0.02
Orgasm	2.3 (2.2)	−1.6 (−2.5 to −0.7)	2.5 (2.2)	−1.3 (−2 to −0.5)	−0.3 (−1.4 to 0.8)	0.56
Satisfaction	2.9 (1.5)	−1 (−1.7 to −0.4)	3.1 (1.6)	−0.5 (−1.1 to 0)	−0.5 (−1.3 to 0.4)	0.25
Pain	1.5 (1.8)	−2.5 (−3.3 to −1.7)	1.4 (1.7)	−1.5 (−2.3 to −0.7)	−1.0 (−2.1 to 0.1)	0.08
Vaginal maturation indexg	28.6 (25.2)	38.4 (27.6 to 49.2)	28.7 (24.7)	4.4 (−2.7 to 11.5)	33.9 (21.3 to 46.6)	<0.01
Vaginal pH	5.4 (0.2)	−0.3 (−0.4 to −0.1)	5.4 (0.2)	−0.2 (−0.3 to −0.1)	−0.2 (−0.3 to −0.1)	0.24

HLA, hyaluronic acid.

^aAnalysis sample size was vaginal estrogen = 23 participants and vaginal HLA = 22 participants; mean difference between groups, adjusted for baseline, is defined as the difference between treatment groups in the change from baseline to 12 wk.

^bP values to test the difference between arms are calculated using the two-sided, two sample t-test, assuming unequal variance.

^cVulvovaginal symptom questionnaire overall score = sum of all the questions.

^dVisual analog scale score is measured by where the participant places an X on a 10-cm line between the end points of “no symptoms” and “extreme symptoms.”

^eVaginal symptom index overall score = sum of all the questions.

^fFemale sexual function index overall score = (Desire domain score*0.6) + (Arousal domain score*0.3) + (Lubrication domain score*0.3) + (Orgasm domain score*0.4) + (Satisfaction domain score*0.4) + (Pain domain score*0.4).

^gVaginal maturation index = (% parabasal cells*0) + (% intermediate cells*0.5) + (% superficial cells*1.0).

In secondary subjective outcomes, the FSFI lubrication score improved more in the vaginal estrogen group as compared with the HLA group (mean difference between arms: −1.2; 95% CI, −2.2 to −0.3; P = 0.02). Other sub-scores of the FSFI, total FSFI, the VAS, and VSI did not indicate clinically meaningful differences between treatment arms after 12 wk of therapy. Across treatment arms, the majority of subjective measures appear to have improved after 12 wk of therapy. Through 12 wk of follow up, a majority of participants across treatment groups reported an improvement of their GSM symptoms after treatment on the PGI-I (Fig. 2: 96% in vaginal estrogen, 91% in vaginal HLA, P = 0.61).

FIG. 2.

Patient global impression of improvement. Patient global impression of improvement scores 1 (very much better), 2 (much better), and 3 (slightly better) were reported as “better” and scores 4 (no change), 5 (slightly worse), 6 (much worse), and 7 (very much worse) were reported as “no change or worse”; ^aP value comparison of vaginal estrogen and vaginal hyaluronic acid (HLA) by Fisher's exact test; analysis sample size was vaginal estrogen = 23 participants and vaginal HLA = 22 participants.

In secondary objective measures, the VMI improved more in the vaginal estrogen group as compared with the HLA group (mean difference between arms: 33.9; 95% CI, 21.3 to 46.6; P < 0.01). The vaginal pH was more acidic after 12 wk of either treatment (mean difference between arms: −0.2; 95% CI, −0.3 to −0.1; P = 0.24).

The duration of follow-up was close to the desired 12 wk on average: 12.3 wk (SD 0.9) in the vaginal estrogen group and 12.4 wk (SD 1.1) in the HLA group (P = 0.58). Treatment compliance was not observed to be different between groups: 95.1% (SD 9.1) in the vaginal estrogen arm and 95.6% (SD 8.2) in the HLA arm (P = 0.84).

No treatment-related serious adverse events occurred in either study group. The adverse events reported in both groups were often mild vaginal symptoms that occurred at the onset of therapy and then self-resolved with continued use (Table 3). The one urinary tract infection in the vaginal estrogen group and the one vulvovaginal candidiasis in the vaginal HLA group were determined to be unlikely related to treatment and were both adequately treated with antimicrobial therapy.

TABLE 3.

Reported adverse events

	Urinary tract infection	Vulvovaginal candidiasis	Vaginal burning or discomfort	Vaginal discharge	Vaginal odor	Vaginal irritation	Other	Total
Vaginal Estrogen n = 23	1	0	1	1	1	0	5	9
Vaginal hyaluronic acid n = 22	0	1	2	1	0	1	3	8

DISCUSSION

In this pilot trial, there were no clinically meaningful differences observed between vaginal HLA and vaginal estrogen for the treatment of GSM after 12 wk. For all participants, GSM symptoms improved after 12 wk of treatment. On overall assessment of treatment impact, over 90% of women in both groups noted improvement on the PGI-I. Both vaginal therapies were well tolerated by participants, with high medication compliance rates, and no serious treatment-related adverse events in either group. The two outcomes with greater improvement in the vaginal estrogen group, as compared with the vaginal HLA group, were the FSFI lubrication sub-score and the VMI.

HLA has long been FDA-approved for the treatment of dry skin, dry eye, and youth-promoting cosmetic products because at a biochemical level, it helps cells retain moisture. In the last two decades, the potential role for HLA in the vagina has also started to be explored in pre-clinical and clinical studies.

However, only a few human studies on vaginal HLA have been conducted, and they have been on small cohorts, with shorter follow-ups than in this study, and have used internationally approved vaginal HLA and vaginal estrogen products.^10,11 Although none of these studies used the vaginal HLA insert that is available in the United States, all of the studies were randomized trials comparing vaginal estrogen and vaginal HLA treatment for GSM. In these studies, both treatments showed improvement in GSM-related parameters, like vaginal symptoms, vaginal pH, and the VMI, after various lengths of treatment exposure (3 to 8 wk). No serious adverse events were reported in any trial with HLA treatment.¹⁰

To the authors' best knowledge, the only United States (U.S.)–based clinical study of vaginal HLA thus far has been on women with GSM symptoms who have a history of endometrial cancer, treated with surgery and adjuvant radiation therapy. In this specific sub-population of women, Carter et al²⁰ showed that vaginal HLA treatment was well tolerated, improved women's confidence about future sexual activity, and improved GSM-related symptoms.

Consistent with prior results but using FDA-approved therapies, our pilot study indicates that treatment with vaginal HLA can not only improve subjective measures related to GSM, but also objective measures, like vaginal pH. However, one of the significant differences we found between treatment groups was that vaginal estrogen improved the VMI more than vaginal HLA. Although this finding is both biologically plausible and consistent with prior studies comparing vaginal estrogen and vaginal HLA, it raises the question of whether subjective or objective measures should be used to determine treatment success for GSM. For example, Davila et al²¹ showed that VMI scores do not correlate with GSM symptom severity.

Based on our own clinical experience with GSM and what we have learned from the pelvic organ prolapse literature, there is a shift toward patient-reported outcomes now because they correlate more with patient satisfaction, treatment adherence, and overall, patient-centered care.²² Therefore, we chose a quality-of-life questionnaire, the VSQ, as the primary outcome for this study, because we thought that the change in their quality of life would be more meaningful and impactful to women in their decision-making about GSM treatment.

The strengths of this study include the longer duration of follow-up than previous studies to ensure that the therapeutic effects of both treatments were captured. The high medication compliance in both groups allowed for a meaningful comparison between cohorts and suggested that GSM treatment is generally well tolerated and desired by women. Additionally, the specific vaginal estrogen and vaginal HLA formulations used in this study are both available and FDA-approved in the U.S., which allows for more applicability of study results.

The limitations of this study include the pilot design of the trial such that the cohort sizes were small, and all participants were recruited from one urban academic center, which may limit the generalizability of the findings. Additionally, participants were provided the vaginal estrogen and vaginal HLA free-of-cost for the duration of this study. Due to variability of medical insurance and medical care across the U.S., cost may be a significant barrier to both treatment options for some women that this study did not take into account. Vaginal estrogen has to be prescribed by a physician, and out-of-pocket costs vary greatly based on insurance coverage. Although vaginal HLA is available over-the-counter in the U.S., it may less reliably be covered by insurance companies.

CONCLUSIONS

In summary, women who suffer from GSM were treated with either vaginal estrogen or vaginal HLA. Both groups noted improvement in symptoms after 12 wk of treatment and the level of improvement observed was not markedly different. Vaginal HLA may be a promising non-hormone alternative for GSM treatment, but larger, adequately powered trials are needed to establish non-inferiority.