Evaluation of the Efficacy and Safety of Hyaluronic Acid Injection for Volume Restoration of the Labia Majora: ESOLANE study

Abstract

Introduction and Hypothesis

Labia majora atrophy and protrusion of the labia minora beyond the labia majora is a concern for an increasing number of women who consider it aesthetically and, sometimes, functionally unsatisfactory. The ESOLANE study was a multicenter clinical investigation designed to collect effectiveness and safety data on DESIRIAL® PLUS injected subcutaneously in the labia majora in participants seeking labia majora volume deficits correction.

Methods

A prospective, uncontrolled, open-label multicenter study was conducted between November 2019 and December 2021. Seventy-three women with labia majora hypotrophy or atrophy and requesting labia majora volume restoration were enrolled and 72 were treated. Outcome measures were collected at baseline, then 4, 12, 24, 36, and 52 weeks post treatment. Primary endpoint was the proportion of patients’ who reported aesthetic improvement on the global aesthetic improvement scale (GAIS) 12 weeks after initial injection. Secondary endpoints were assessments of patients’ and investigators’ who reported GAIS, patient sexual function and physical symptoms, patient satisfaction, and safety.

Results

According to the patients’ who reported GAIS, 97% rated themselves as improved 12 weeks following the initial treatment. Improvement levels were high throughout the 52-week follow-up period with rates > 92%. Improvements were also confirmed on investigators’ assessments with rates > 86%. Furthermore, patients reported significantly improved sexual function, symptom reduction, and high satisfaction. DESIRIAL® PLUS was well tolerated.

Conclusions

DESIRIAL® PLUS is an effective and safe treatment option in patients with labia majora hypotrophy or atrophy. This effect goes beyond aesthetic improvement, as treatment was associated with improvement in patients’ physical symptoms and sexual function.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00192-025-06094-1.

Introduction

The labia majora consist mainly of connective tissue and subcutaneous adipose tissue, and hence, are affected by factors that reduce hyaluronic acid (HA), collagen and fat, such as genetic predisposition, some diseases, and the aging process [1, 2]. This results in volume loss, reduced tissue elasticity and alteration in the labia minora to majora ratio [1–3]. Although there is a correlation between the individual’s characteristics, like the body mass index (BMI), it is recognized that there is wide inter-personal variation in the shape and size of the external genitalia irrespective of such characteristics [4, 5]. Nonetheless, increasing numbers of women are concerned about the shape, size, or proportions of their vulva [6, 7], where patients prefer that the labia minora would not protrude beyond the labia majora [7, 8]. Although there is nothing unusual about such a protrusion, it is regarded by some as aesthetically and, sometimes, functionally unsatisfactory, resulting in reduced sexual self-esteem and psychosocial impairment and physical discomfort [3]. Furthermore, the association between symptoms of irritation, burning, itching, and dyspareunia with labial atrophy is well documented, at least, as part of the genitourinary syndrome of the menopause [9].

With the increasing recognition of the importance of a woman’s self-image and sexual satisfaction for her well-being, the demand for female genital aesthetic procedures has been growing steadily over the past decade, particularly for less invasive procedures [10].

The protrusion of the labia minora beyond the majora can be surgically managed by labioplasty to reduce the size of the labia minora [7, 11]. However, this intervention has been associated with risk of bleeding, impaired sensitivity at the surgical site, and a relatively long recovery time [10, 12, 13]. Furthermore, labia minora reduction might not be desirable if the dissatisfaction is due to labia majora atrophy, where labia majora augmentation is a better alternative for correcting the resulting labial disproportion [14]. This augmentation can be performed surgically using different procedures, including lipofilling labia minora transposition into the labia majora, dermal grafts and, rarely, adipofascial flaps [3, 11, 14, 15]. However, these procedures have been associated with several adverse events (AEs), including pain, hematomas, flap necrosis, wound breakdown, infections, asymmetry, and extensive scarring [14].

More recently, less invasive procedures, such as the subcutaneous injection of cross-linked HA [1, 15–17] and calcium hydroxylapatite [18] have been investigated. Although touch-up treatments are often needed, calcium hydroxylapatite and cross-linked HA injections have been associated with satisfactory clinical results, favorable safety profile, and hence gaining popularity among patients and clinicians [1, 17–19].

HA is a glycosaminoglycan found in the extra-cellular matrix of the skin and connective tissues providing hydration for the skin and mucosa. When injected, HA also induces collagen synthesis by stimulating fibroblast activity through a mechanical pressure effect on these cells [20, 21]. Furthermore, HA has a low-risk potential for allergies and immunogenic reactions, as it has no antigenic tissue specificity [22]. DESIRIAL® PLUS (Laboratoires VIVACY, France), is a resorbable injectable 21 mg/g gel-based cross-linked HA licensed in Europe and in other countries for the aesthetic purpose of labia majora volume restoration in cases of hypotrophy or atrophy of the vulvar labia majora (CE marked in 2011). As DESIRIAL® PLUS is an implant injected into the body, it is classified as a class III medical device. Class III devices are subject to the most stringent regulatory controls, requiring extensive evidence for safety and effectiveness before they can be approved for use. DESIRIAL® PLUS obtained the CE-marking in 2011 following the fulfillment of all essential requirements for its use with a demonstrable favorable benefit–risk ratio.

A previous pilot study involving 35 patients has generated promising data on efficacy and tolerability of DESIRIAL® PLUS for labia majora volume restoration (unpublished data, Laboratoires VIVACY, France). Building on this pilot, the ESOLANE study was designed as a larger multicenter clinical investigation to collect effectiveness and safety data on DESIRIAL® PLUS in participants seeking to correct labia majora volume deficits.

Materials and Methods

This was a prospective, uncontrolled, open-label multicenter study conducted in nine centers between November 2019 and December 2021. This study was performed in accordance with the ethical standards of the Declaration of Helsinki on medical research in human subjects. The applicable institutional review board approved the study protocol, the study was registered, and all participants provided written informed consent. Participants were informed that an HA-based product marketed for labia majora volume restoration would be injected subcutaneously in the labia majora for correction of volume deficit. This augmentation could lead to aesthetic improvements of their vulvar area. Additionally, they were informed that the procedure could potentially reinforce the protective function of the labia majora. Patients were also made aware of the possible side effects that would mostly be of mild or moderate intensity, such as inflammatory reactions (which tend to resolve in a few days), nodules, post-injection pain, local mobility of the implant, and hematomas.

Female patients ≥ 18 years old, with labia majora hypotrophy or atrophy and requesting labia majora volume restoration were considered potentially eligible for inclusion into the study. Labia majora atrophy and hypotrophy relates to the total or partial loss of labia majora volume and hence relied on patient’s perception and the operator’s assessment. Additionally, the protrusion of the labia minora beyond the labia majora was also used as a significant objective assessment to confirm the diagnosis. Pregnant or breastfeeding women, women with a tendency to develop hypertrophic or keloid scars, women with known hypersensitivity to the investigational device or to any other product planned to be used in the study, women with active or recurrent genital infection (e.g., genital herpes, candidiasis, bacterial vaginosis), women suffering from hemostatic disorder, women with a history or ongoing auto-immune disease, women with a history of cancer in areas close to the injection site (vulvar or anal cancers), or with an ongoing cancer or presence of pre-cancerous cells were excluded. At baseline, data on participants’ demographics, medical history, and examination were collected.

A total of seven visits were planned at each participating center. The first visit was an optional screening visit and was followed by a baseline visit, during which all patients received treatment with DESIRIAL® PLUS injected in the subcutaneous fat tissue along the longitudinal axis of the labia majora using an 18-gauge cannula and the linear retrotracing technique, by physicians with previous significant experience in the use of DESIRIAL® PLUS in their daily practice. Depending on the operator’s position and preference, it was possible to insert the cannula into the labia majora either anteriorly or posteriorly (Fig. 1). Four weeks after this visit, patients were given the option of a touch-up injection if deemed necessary by both the investigator and the patient to correct any residual asymmetry or irregularity. The maximum authorized total volume of injected product was 6 mL (2 mL per labium at baseline, and 1 mL per labium at week 4). It was possible to use topical or local anesthetic depending on the participant’s wishes and the clinician’s decision. Follow-up evaluations were done at weeks 12, 24, 36, and 52.

Fig. 1.

Injection cannula entry points into the labia majora. It was possible to insert the 18-gauge cannula anteriorly or posteriorly into the labia majora, depending on the position and preference of the operator. DESIRIAL® PLUS was injected in the subcutaneous fat tissue along the longitudinal axis of the labia majora using the linear retrotracing technique

Aesthetic improvement was evaluated at each follow-up visit. Patients (aided by mirror self-assessment) and investigators completed a Global Aesthetic Improvement Scale (GAIS) to assess aesthetic improvement in appearance compared to pretreatment. GAIS is a standardized and validated 5-point Likert scale ranging from “very much improved” to “worse.” A lower GAIS score indicates better improvement. For the analysis, any of the first three options (“very much improved,” “much improved,” “improved”) were considered an indication of improvement. Patients’ satisfaction with the treatment was assessed using a Patient Satisfaction Questionnaire (PSQ), which comprised six questions with scores ranging from 1 (not at all) to 4 (totally). The PSQ included questions about the patient’s satisfaction with the results of the treatment, whether they would use the treatment again if they needed to do so, if the treatment had given them more confidence in themselves and their intimate life, if their labia majora was firmer, and if their labia minora was less visible. Related to the last question, there was an additional complementary question if patients answered yes asking whether they were satisfied with the appearance. Sexual function was evaluated by patients at baseline and at each follow-up visit using the Female Sexual Function Index (FSFI) (19 multiple choice questions which evaluate 6 domains of desire, arousal, lubrication, orgasm, satisfaction, and pain) [23]. Symptoms related to the atrophy of the labia majora (irritation/burning during daily life, irritation/burning during sport, and itching) were quantified using a Numerical Rating Scale (NRS) (scores from 0 [absence of a symptom] to 10 [intolerable symptom]). Safety of DESIRIAL® PLUS was evaluated through the collection of AEs throughout the study and the assessment of pain related to each injection using an 11-point NRS where “0” and “10” equated to no and worst possible pain, respectively.

The primary endpoint of this study was the proportion of patients who reported (self-assessed) aesthetic improvement on GAIS 12 weeks after initial injection. The secondary endpoints included GAIS scores reported by patients, GAIS scores reported by the investigator after visual examination, patients reported FSFI and PSQ scores, and any reported symptoms at all follow-up timepoints.

Statistical Analysis

The expected percentage of improvement was not known a priori as there were no previous estimates of labia majora aesthetic improvement following comparable treatment options. Hence, we used patient reported improvement frequencies following aesthetic facial treatments as a guide. These rates were reported to be > 90% up to 6 months post treatment [24–27]. Assuming a slightly more conservative estimate of 85% for the purpose of this study, a sample size of 48 patients with complete efficacy assessments would provide 10% accuracy of the 95% confidence interval (CI) for the analysis of the primary endpoint. Assuming that 20% had efficacy assessments affected by changes in study conduct due to COVID-19 restrictions and assuming a lost to follow-up rate of 15%, the number of patients required to be included in the study was 71.

The statistical analyses were performed using SAS® software (SAS Institute, Cary, North Carolina, United States of America, Version 9.4 or higher). Continuous data were summarized using means, standard deviation (SD), median, and interquartile ranges. Categorical data were presented as counts and frequencies. The level of significance was set at 0.05 and the 95% CI was computed where applicable.

Results

Recruitment and Participants’ Characteristics

Overall, 73 patients were enrolled into the ESOLANE study, of whom 72 were treated with DESIRIAL® PLUS at baseline. Of these, 67 (93.1%) provided follow-up data at 12 weeks. A total of 54 (75.0%) patients attended all planned follow-up visits. Reasons for not completing the study included lost to follow–up, the COVID-19 pandemic, and exclusion by the sponsor because of nonfulfillment of eligibility criteria in 8 (11.1%), 6 (8.3%), and 3 (4.2%) participants, respectively. An additional patient withdrew due to pregnancy. The study flowchart and analyses sets are presented in Fig. 2.

Fig. 2.

Study flowchart and analyses sets (COVID-19 Coronavirus disease 2019, FAS full analysis set (included all treated patients who had at least one post-baseline evaluation of an efficacy endpoint), N total number of patients, PPS per protocol set (included all patients from the FAS population without major protocol deviation that might significantly affect the completeness, accuracy, and/or reliability of the study data. Major protocol deviations are defined as deviations that could impact the primary efficacy criterion based on the global aesthetic improvement scale (GAIS) evaluated by the patient 12 weeks after baseline injection), SAS safety analysis set (all patients who were injected with study treatment at first visit), V visit)

Demographic and Baseline Characteristics

At baseline, study participants had a mean age of 45.3 (SD 11.17; range 23–69) years and a mean BMI of 22.03 (SD 3.41; range 16.4–32.8). The mean total FSFI at baseline was 22.70 (SD 9.10; range 3.6–34.6).

Injection Characteristics

The mean total volume of DESIRIAL® PLUS injected at baseline was 3.94 (0.47) mL (1.97 [0.24] mL on the right side and 1.98 [0.24] mL on the left side). A total of 36 (50%) participants had touch-up injections at the 4-week follow-up visit (bilateral in 34 and unilateral in 2). The mean total volume of DESIRIAL® PLUS used for touch-up was 2.10 (0.75) mL with comparable volumes between both sides. For most patients, at baseline and touch-up visits, injection was performed via an anterior entry point into the labia majora. Anesthesia was used for all patients treated at baseline and at week 4.

Effectiveness Outcomes

On the GAIS, 65 of the 67 participants (97% [89.6; 99.6]) rated themselves as “improved,” “much improved,” or “very much improved” at week 12 (3A). A worst-case imputation sensitivity analysis, assuming that all patients with missing GAIS assessments at 12 weeks considered themselves not improved, showed an improvement rate of 90.3% [81.0; 96.0]. Analysis of the primary outcome in the PPS was comparable to that obtained from the FAS (96.1% [86.5; 99.5]).

The improvement rate remained high till week 52 (92.2%), with a maximum reached at week 24 (98.4%) (Fig. 3A). The investigators’ evaluations on the GAIS over 52 weeks were consistent with the patients’ self-evaluation with all investigators rating the aesthetic improvement as “improved,” “much improved,” or “very much improved” at 4, 12, and 24 weeks, and with the rating remaining high at week 52 (86.8%) (Fig. 3B).

Fig. 3.

Participants’ reported (A) and investigators’ reported (B) GAIS (FAS, N = 72) (FAS full analysis set, GAIS global aesthetic improvement scale, V visit)

FSFI scores revealed significant improvement at each of the follow-up timepoints. The mean (SD) FSFI score was 22.70 (9.10) before the first treatment. The scores obtained at 4, 12, 24, 36, and 52 weeks were 25.25 (9.60), 27.59 (8.23), 27.31 (8.47), 27.66 (7.27), and 28.93 (7.44), respectively. The change in the mean full-scale scores at each timepoint from baseline were 2.61 (8.76), 4.25 (6.75), 4.06 (9.10), 5.24 (8.53), and 5.59 (8.62) at 4, 12, 24, 36, and 52 weeks, respectively, and these were all statistically significant (p < 0.001). There was also an increase in the mean score for each of the six individual FSFI domains at all follow-up timepoints compared to baseline. These increases were all statistically significant except for the satisfaction domain at the 4- and 36-week follow-up timepoints (Table 1).

Table 1.

FSFI full and sub-domain scores at baseline and follow-up timepoints (FAS, N = 72)

Parameter	V1—Pre-injection	V2—Week 4*	V3—Week 12	V4—Week 24	V5—Week 36	V6—Week 52
Full scale
Score—n	68	65	62	59	54	50
Mean (SD)	22.70 (9.098)	25.25 (9.603)	27.59 (8.228)	27.31 (8.473)	27.66 (7.273)	28.93 (7.435)
Change from baseline—n		62	58	56	51	48
Mean (SD)	–	2.61 (8.756)	4.25 (6.746)	4.06 (9.104)	5.24 (8.533)	5.59 (8.615)
p value	–	< 0.001***	< 0.001***	< 0.001***	< 0.001***	< 0.001***
Desire domain
Score—n	71	68	66	64	58	53
Mean (SD)	3.58 (1.322)	3.99 (1.185)	4.19 (1.155)	4.33 (1.066)	4.27 (1.195)	4.54 (1.138)
Change from baseline—n		67	65	63	57	53
Mean (SD)	–	0.43 (1.204)	0.54 (1.306)	0.73 (1.313)	0.78 (1.379)	0.92 (1.281)
p value	–	0.003**	0.002**	< 0.001***	< 0.001***	< 0.001***
Arousal domain
Score—n	71	68	66	64	59	52
Mean (SD)	3.55 (1.740)	3.98 (1.933)	4.40 (1.680)	4.35 (1.763)	4.46 (1.638)	4.53 (1.552)
Change from baseline—n		67	65	63	58	52
Mean (SD)	–	0.47 (1.790)	0.76 (1.594)	0.75 (2.165)	0.91 (2.206)	0.95 (1.774)
p value	–	0.003**	< 0.001***	< 0.001***	< 0.001***	< 0.001***
Lubrication domain
Score—n	71	68	66	63	58	52
Mean (SD)	3.93 (2.021)	4.33 (2.099)	4.74 (1.902)	4.66 (1.980)	4.90 (1.700)	5.06 (1.608)
Change from baseline—n		67	65	62	57	52
Mean (SD)	–	0.47 (1.847)	0.73 (1.509)	0.66 (2.030)	1.05 (2.153)	1.04 (1.755)
p value	–	< 0.001***	< 0.001***	< 0.001***	< 0.001***	< 0.001***
Orgasm domain
Score—n	70	68	66	63	59	52
Mean (SD)	3.43 (2.096)	3.91 (2.193)	4.46 (1.941)	4.25 (2.075)	4.48 (1.724)	4.63 (1.817)
Change from baseline—n		67	64	62	58	52
Mean (SD)	–	0.51 (1.980)	0.94 (1.565)	0.72 (2.217)	1.02 (2.102)	1.16 (2.187)
p value	–	0.002**	< 0.001***	0.003**	< 0.001***	< 0.001***
Satisfaction domain
Score—n	68	65	62	59	55	51
Mean (SD)	4.07 (1.547)	4.36 (1.734)	4.79 (1.558)	4.68 (1.569)	4.52 (1.706)	5.04 (1.400)
Change from baseline—n		62	58	56	52	49
Mean (SD)		0.30 (1.593)	0.65 (1.568)	0.61 (1.856)	0.49 (2.005)	1.00 (1.855)
p value		0.051	< 0.001***	0.012*	0.053	< 0.001***
Pain domain
Score—n	69	68	65	62	59	52
Mean (SD)	3.76 (2.086)	4.18 (2.245)	4.46 (1.968)	4.49 (2.045)	4.19 (2.086)	4.52 (2.050)
Change from baseline—n		66	62	60	57	51
Mean (SD)	–	0.52 (2.242)	0.61 (1.841)	0.64 (2.157)	0.44 (2.190)	0.81 (2.056)
p value	–	0.028**	0.001**	0.004**	0.025*	< 0.001***

FAS full analysis set, FSFI female sexual function index, N total number of patients, n number of patients with available data, Q1 first quartile, Q3 third quartile, SD standard deviation, V visit, p values calculated using Wilcoxon signed-rank test, * Assessment performed before the optional touch-up injection

^* if p ≤ 0.05, ** if p < 0.01, *** if p < 0.001

When considering each PSQ item and all follow-up visits, the most frequently reported levels of satisfaction overall were “a lot” and “totally” indicating participants’ satisfaction (Fig. 4 and Supplementary Table S1).

Fig. 4.

Patient Satisfaction Questionnaire scores for questions 1, 3, 4, and 5 at different follow-up timepoints (FAS, N = 72) (FAS full analysis set, N total number of patients, V visit)

Compared to baseline, the mean scores of patients’ reported symptoms related to labia majora hypotrophy or atrophy (irritation/burning during daily life, irritation/burning during sports, itching) significantly improved from as early as 4 weeks following treatment and this improvement was sustained throughout the whole 52-week study follow-up period (Fig. 5). For all three symptoms, the largest decrease was obtained at week 52. For irritation/burning during daily life, the mean scores were 2.9 (2.64) at baseline and 1.0 (1.97) at week 52, while for irritation/burning during sports, the mean scores were 3.1 (2.80) at baseline and 1.0 (1.86) at week 52, and for itching, these were 2.5 (2.88) and 0.9 (1.97) at baseline and at week 52, respectively (p values ranged from 0.005 to < 0.001) (Fig. 5). A sample of before and after treatment photographs are presented in Fig. 6.

Fig. 5.

Patient reported symptoms at different follow-up timepoints (FAS, N = 72) (SD standard deviation, V visit, * if p ≤ 0.05; ** if p < 0.01; *** if p < 0.001 (Wilcoxon signed-rank test for the change from V1). Patient’s symptoms are rated using a numerical rating scale from 0 (absent) to 10 (intolerable) in increments of 1)

Fig. 6.

Before and after treatment photographs (A) Pre-treatment photograph of a 58-year-old woman with labia majora hypotrophy. (B) Twelve-weeks and (C) 52 weeks post-treatment photographs of the same patient after one injection of 2 mL of study product in each labium majus at baseline. (D) Pre-treatment photograph of a 32-year-old woman with labia majora atrophy. (E) 12 weeks and (F) 52 weeks post-treatment photographs of the same patient after the injection in each labium majus of 2 mL of study treatment at baseline and 1 mL 4 weeks after first injection. (G) Pre-treatment photograph of a 59-year-old woman with labia majora atrophy. (H) 12 weeks and (I) 52 weeks post-treatment photographs of the same patient after the injection in each labium majus of 2 mL of study treatment at baseline and 1 mL 4 weeks after first injection

The results obtained from analyses of the different outcomes in the PPS were comparable to those reported in the FAS and efficacy evaluable set (FAS without any participants with COVID-19 related protocol deviations) (data not shown).

Safety

The mean patient’s assessed injection-related pain scores using an 11-point NRS at baseline and touch-up injections were 2.8 (2.58) and 2.6 (2.28), respectively.

A total of 11 (15.3%) patients experienced 14 treatment-related AEs. Of these events, 11 were of mild intensity and three were of moderate intensity. None of these led to study discontinuation and there were no reported treatment-related AEs of severe intensity or procedure-related AEs. These AEs included vulval hematoma and vulval edema in two (2.8%) patients (2 events each), vulvovaginal dryness and vulvovaginal pain in one (1.4%) patient each, injection site induration, injection site inflammation and injection site pain in one patient (1.4%) each, vulvovaginal mycotic infection in one (1.4%) patient, pre-syncope episode in one (1.4%) patient and ecchymoses in one (1.4%) patient. The patient who had vulvovaginal mycotic infection reported undertaking a 2-h indoor training session at the gym on the same day following her treatment, which was against the medical advice provided prior to injection. Hence, this isolated event was considered to be possibly related to the patient’s physical exercise.

Most treatment-related AEs resolved within 8 days. Three patients (4.2%) had one treatment-related AEs that lasted longer than 30 days. The first patient had injection site pain that lasted 130 days, the second one had injection site induration that lasted 93 days and the third one had injection site inflammation that lasted 64 days. Two serious AEs not linked to the study treatment or procedures were reported during the study period.

Discussion

Laboratories VIVACY were the first to be granted the CE-marking for gynecological applications of HA injectables. Throughout the ESOLANE study, the DESIRIAL® PLUS injections were performed in compliance with the device’s instructions for use, according to the general recommendations of treatment with HA fillers, and by physicians with a previous significant experience in the use of DESIRIAL® PLUS in their daily practice. The primary endpoint of this study was the proportion of patients considering themselves improved at week 12. According to the patients’ self-evaluations on the GAIS, 97% rated themselves as improved 12 weeks following the initial treatment. Improvement levels were high throughout the follow-up period (> 92%) with the highest and lowest rates of 97% and 92.2% reported at 24 and 52 weeks post the initial injection, respectively. The increase in the proportion of improved patients after week 4 is expected, given that those who required touch-up injection received them at week 4, which optimized their aesthetic improvement. It is also possible that this increase reflects the gradual, rather than immediate, mechanism of action of HA fillers whereby they attract and bind water molecules. The gradual decrease in the proportion of improved patients from week 24 onward is also expected, owing to the resorbable nature of HA fillers [22].

In this study, the improvement results of investigators’ and patients’ GAIS evaluations were high and comparable (> 86% and > 92% improvement respectively), and patient’s satisfaction (> 88%) was high over 52 weeks post treatment initiation. Our findings concur with those of Zerbinati et al. who undertook a retrospective analysis of 37 patients with labia majora atrophy treated with another type of HA filler [17]. The authors reported that post injection, all participants and investigator were satisfied with the aesthetics of the intimate area based on assessments on a visual analogic scale. However, the follow-up timepoints were not specified in the study [17]. Similarly, Fasola and Gazzola retrospectively analyzed GAIS numerical scores of 54 patients treated with HA fillers (DESIRIAL® and DESIRIAL® PLUS) for labia majora hypotrophy and reported mean scores of 8.70 and 8.52, as assessed by patients and investigators on a 10-point scale 12 months post treatment [1]. The results of these studies support our findings and indicate that subcutaneous HA fillers injections are effective in improving aesthetic outcomes in patients complaining of labia majora atrophy up to 52 weeks post treatment initiation.

In addition to the aesthetic impact, several functional outcomes were also assessed. The FSFI scores at baseline ranged between 3.6 and 34.6 (data not shown). However, despite this baseline heterogeneity in sexual functions, the mean FSFI score obtained at each post-treatment timepoint was significantly higher than that obtained at baseline, indicating improvement in sexual function. An FSFI full scale score ≤ 26.55 indicates sexual dysfunction [23]. Hence, most patients included in the ESOLANE study had a degree of sexual dysfunction at baseline. In contrast, the median FSFI full scale scores were above this cutoff at all subsequent follow-up timepoints, including at 4 weeks prior to any touch-up treatments. Of note, > 75% of our study patients had FSFI full scale scores > 26.55 at the 12- and 52-week follow-up appointments (Q1 = 26.60 at week 12 and Q1 = 27.70 at week 52, data not shown) indicating the absence of sexual dysfunction. A similar trend was also observed when considering the individual FSFI domains. To our knowledge, there are no published studies evaluating patients’ sexual function before and after treatment of labia majora atrophy with HA fillers. In the study by Zerbinati and colleagues, they assessed dyspareunia using a patient reported pain visual analogue scale and the results demonstrated that a higher percentage of patients reported being pain free post- compared to pre-treatment (89% vs. 33%) [17]. Reduced sexual self-esteem and psychosocial impairment were previously reported in patients with labia majora atrophy [14].

Functional benefits were also confirmed by patients reported improvements in labial atrophy-related symptoms (reduced itching, burning, irritation). These results indicate that the benefits of DESIRIAL® PLUS go beyond aesthetic ones and include significant improvements in patients’ everyday comfort and psychosocial aspects of their life. Such results (i.e., presence of both aesthetic and functional benefits) were not reported in any previous studies related to HA injection. Volume restoration of labia majora could reinforce their initial role of protecting the labia minora and introitus, thus contributing to a better vulvar trophicity. Additionally, the labia minora and majora contain sweat and sebaceous glands producing lubricating secretions reducing vaginal friction, increasing comfort during sexual intercourse and minimizing any feelings of soreness or irritations [28]. It is also possible that volume restoration of the labia majora could contribute to the retention of such functional secretions. It could also contribute to the maintenance of labia majora turgescence observed during sexual arousal [28]. Despite these potential functional benefits, DESIRIAL® PLUS should only be used within its current license indications, and hence, not a first line or mainstream treatment for female sexual dysfunction or genitourinary syndrome of the menopause.

The procedure’s effects last 12 months in the patients. DESIRIAL® PLUS was formulated to achieve sufficient rheological properties to ensure a visible aesthetic correction and to make this correction long-lasting. Indeed, our results are consistent with those of a randomized study evaluating the use of a product with mechanical parameters and cross-linking levels similar to those of DESIRIAL® PLUS for nasolabial fold correction which demonstrated effects lasting for over 12 months [29]. Hence, the effect observed in our study is expected to last for a comparable period. In terms of tissue remodeling, previous studies in skin in human and animal models with NASHA and cross-linked injectable HA have shown a stimulation of production of extracellular matrix components, such as collagen and elastin, that is already visible after 4 weeks [22]. A more recent study in vaginal mucosa in humans with cross-linked injectable HA (DESIRIAL®) has also shown the stimulation of CoL1A1 and CoL3A1 gene expression at 8 weeks after injection, suggesting stimulation of collagen formation [30].

Treatment-related AEs following the treatment of atrophy of the labia majora with HA fillers has not been the main focus of any published prospective studies to date, and hence their incidence remains unknown. Studies that explored this treatment option reported events of mild intensity only, such as swelling [17], edema, and ecchymosis [1]. However, both studies comprised retrospective analyses, which could have introduced bias into their findings. Overall, our study demonstrated that DESIRIAL® PLUS was well tolerated, with most treatment-related AEs being of mild to moderate intensity.

The main strengths of ESOLANE lie in the prospective design, the multi-centricity, the sample size, and the use of a combination of patients’ and investigators’ reported outcomes. However, we recognize that the gold standard methodological design to assess the efficacy of an intervention is a randomized controlled trial. Given the absence of marketed HA-based fillers suitable for comparison, such a design was not feasible. We also appreciate that our study could have been strengthened using independent blinded evaluators to mitigate the risk of potential bias. Nevertheless, the magnitude and consistency of reported improvement strengthens the validity of the study findings.

Conclusion

This study demonstrated that DESIRIAL® PLUS is an effective and safe treatment option in patients with labia majora hypotrophy or atrophy. This effect goes beyond aesthetic improvement by improving patients’ physical symptoms and sexual function. These improvements were sustained for 52 weeks following the initial treatment, with a slight decrease in reported benefits starting from 24 weeks. A clinical study assessing the potential functional benefits of this treatment as the primary outcome could be of particular interest.

Supplementary Information

Below is the link to the electronic supplementary material.

Authors’ Contribution

F Boucher: Supervision, conceptualization, investigation, validation, manuscript writing and editing.

C Eychenne: Conceptualization, investigation, validation, manuscript writing and editing.

B Gurriet: Investigation, validation, manuscript editing.

N Berreni: Conceptualization, investigation, validation, manuscript editing.

J Berrocal: Investigation, validation, manuscript editing.

P Foulc: Investigation, validation, manuscript editing.

A Levy: Investigation, validation, manuscript editing.

A Guzman-Ruiz: Investigation, validation, manuscript editing.

B Hersant: Conceptualization, investigation, validation, manuscript editing.

Funding

This study was funded by Laboratoires VIVACY, 252 rue Douglas Engelbart, Archamps Technopôle, 74160 Archamps, France. Funding was utilized for study design, conduct, data analysis, medical writing, and manuscript submission.

Declarations

Ethical Statement

The study received French ethics committee approval on 06 September 2019 (Comité de Protection des Personnes EST-III, 19.09.02/SI, CNRIPH 19.05.02.61300, ID-RCB 2019-A01241-56) and was registered with ClinicalTrials.gov (www.clinicaltrials.gov, NCT 04147689).

Conflicts of Interest

All authors were study investigators and had contracts with Laboratoires VIVACY either directly or through their institution for participation in the study (including fees for patient recruitment and follow-up, as well as provision of study products). FB was remunerated by Laboratoires VIVACY for coordinator activities in this study. FB, NB, JB, and BH received travel expenses and/or honoraria from Laboratoires VIVACY. CE was remunerated by Laboratoires VIVACY for acting as a consultant and by TEOXANE for participating in research.