Prospective, multicenter, uncontrolled study on the effectiveness and safety of a hyaluronic acid water-based vaginal lubricant in alleviating vaginal dryness and dyspareunia

Abstract

Background

Vaginal dryness (VD) represents a significant concern affecting women across diverse life stages, encompassing both pre- and postmenopausal women at any age. Dyspareunia, defined by genital pain that can be experienced before, during, or after intercourse, is often associated with vaginal dryness.

Aim

This study aimed to evaluate the effectiveness and safety of a water-based vaginal lubricant with hyaluronic acid to reduce sexual discomfort associated with vaginal dryness.

Methods

A prospective, multicenter, uncontrolled clinical investigation was conducted over a three-month period in women aged 18 years or older experiencing pain or difficulty during sexual intercourse for whom the use of a vaginal lubricant was recommended.

Results

Significant improvements were observed in the FSFI scores, indicating enhanced sexual function (p < .001). Vaginal dryness symptoms, including irritation, dryness, itching, and dyspareunia, significantly decreased after product use (p < .001).

Clinical implications

This study contributes to the limited scientific knowledge on the application of lubricants in the context of symptoms associated with VD.

Strengths & limitations

In addition to the short study period, inherent limitations of the study design, and lack of placebo control, it is pertinent to acknowledge that some of the pros used in this study were not based on validated questionnaires. However, as far as we know, this study is the only one that analyzes well-being and sexual pleasure as results using a lubricant formulated with hyaluronic acid.

Conclusion

This tested vaginal lubricant with hyaluronic acid has demonstrated efficacy in improving vaginal dryness and female sexual function, particularly in reducing pain and improving lubrication during sexual intercourse, and showed a favorable safety profile, with minimal and transient adverse events.

Keywords:

• Vaginal dryness
• dyspareunia
• sexual intercourse
• lubricant
• hyaluronic acid

Introduction

Vaginal dryness (VD) represents a significant concern affecting women across diverse life stages, encompassing both premenopausal and postmenopausal cohorts irrespective of age [1]. Studies have highlighted that more than half of women aged above 51 experience varying degrees of VD, often attributed to diminished estrogen levels. Intriguingly, approximately 17% of premenopausal women aged between 17 and 50 encounter sexual intercourse difficulties linked to VD and painful experiences [2,3].

Dyspareunia, a medical term used to describe painful sexual intercourse, is a prevalent and frequently overlooked female health issue [4]. It exhibits a global prevalence ranging from 3% to 18%, with a substantial impact on 10% to 28% of individuals over their lifetime [4]. Dyspareunia can be influenced by a multitude of factors, encompassing age (particularly women aged 50 years and older), as well as structural, inflammatory, infectious, neoplastic, traumatic, hormonal, and psychosocial conditions [4]. The impact of dyspareunia extends beyond the physical and sexual realm [1], often resulting in depression, anxiety, heightened pain sensitivity, negative body image, and diminished self-esteem [3,5].

These findings underscore the multifaceted nature of VD, emphasizing its impact on women at different life phases and emphasizing the imperative for comprehensive interventions that address this condition across age groups. To effectively manage this condition, it is crucial to adopt a comprehensive and individualized approach that addresses all aspects of pain, including physical, emotional, and behavioral factors [6,7]. The first line of treatment for symptoms such as dyspareunia due to VD involves the use of moisturizers, especially those containing hyaluronic acid (HA), and lubricants [8,9], as well as other formulations that can help create an environment conducive to natural lubrication [10]. These products play a pivotal role in not only moisturizing the vaginal region but also fostering mucosal flexibility and elasticity [9,11]. There exists promising evidence supporting the efficacy of vaginal lubricants and gels in alleviating the discomfort associated with VD [11–14]. The current corpus of high-quality evidence pertaining to their efficacy in alleviating dyspareunia in women remains limited.

Emerging evidence suggests that HA has the ability to adhere to the vaginal wall and bind with a considerable quantity of water, facilitating hydration of the tissue [15–18]. The study of HA has witnessed a surge in recent years, particularly in its application for alleviating conditions such as VD [19], postmenopausal vaginal atrophy [20], and chronic vulvar fissure [21].

The investigational device, namely Cumlaude Lab Mucus Gel® (CLMG), consists of a lubricant for facilitating intercourse. It is composed of an aqueous base of hydrating agents: hyaluronic acid and diglycerin. Synthetic acrylamide polymers possess lubricating and filmogenic action; together with the GUM-1 biosaccharide with hydrating and desensitizing properties, it prevents irritation and reduces itching and burning sensation. It has a pH and consistency similar to those of the physiological vaginal secretions, strictly followed the guidelines outlined by the WHO [22]. It has been dermatologically tested and its use is compatible with latex condoms. It therefore can be used frequently as required by the patient.

The primary objective of this study is to gather comprehensive effectiveness and safety data concerning the application of CLMG in reducing difficult intercourse and alleviating dyspareunia symptoms, including the improvement of sexual well-being and pleasure, resulting from VD.

Methods

Investigational device description

The investigational device (Cumlaude Lab: Mucus Gel®. DERMOFARM, S.A.U. Rubí (Barcelona), Spain) consists of a lubricant for facilitating intercourse in case of painful intercourse that occurs with vaginal dryness.

Composition: active ingredients of the investigational device

• sodium hyaluronate

• diglycerin

• acrylamide copolymer

• biosaccharide gum-1

Study design and population

Prospective, multicenter, uncontrolled clinical investigation with a CE-marked medical device under normal conditions of use to evaluate the effectiveness of the vaginal lubricant in reducing the severity of pain or difficulty in sexual intercourse and improve of sexual well-being and pleasure with 3 months of follow-up.

To be eligible for inclusion in the study, women had to be met the following inclusion criteria:

• Women over 18 years of age.

• Women complaining of pain or difficulty in sexual intercourse where the use of a vaginal lubricant is advisable.

• Women not using any topical or vaginal moisturizing treatment for at least 7 days prior to the start of the study and who agree not to use it during the study period.

• Patients who have not used vaginal lubricants in the past 15 days.

• Women for whom the decision of the physician to prescribe the lubricant gel is independent of their participation in this study.

• Patients who agree to participate and give their written informed consent.

The exclusion criteria encompassed patients who had recently initiated hormone replacement therapy (HRT) within the past two months or had planned changes to their HRT. It also excluded women currently using or having used a vaginal lubricant in the past 15 days and those reporting a frequency of sexual intercourse less than two times per month. Patients with infectious vaginitis, sexually transmitted diseases, known intolerance or allergy to any components of the lubricant, or any clinical disorder or disease that, in the physician’s judgment, could jeopardize the patient or interfere with the study results were excluded.

All patients who met the inclusion and exclusion criteria were enrolled in the study between June 1st and September 30th, 2022.

The patients underwent evaluation by a qualified gynecologist, who meticulously assessed the fulfillment of the inclusion and exclusion criteria, delivered the treatment, provided comprehensive details regarding all aspects of the clinical investigation, and furnished the patients with the necessary information sheet and informed consent.

The lubricant must be used as needed by the woman, whenever she needs it, only during intercourse, for a period of three months.

Patients were longitudinally observed over a period of three months, wherein they attended scheduled clinical appointments at baseline (study initiation) and at the end of the study visit (month 3). A telephone visit was conducted during week 4 to evaluate the progression of the participants.

Objectives and variables

The primary objective of this study was to assess the change in the Female Sexual Function Index (FSFI) between the baseline visit and the three-month visit. A higher score indicates improved sexual function, with a maximum score of 36 points and a minimum of 0 points (no sexual activity) (Primary Outcome) [23]. Secondary effectiveness endpoints were the change in the severity score of symptoms of dyspareunia, irritation, dryness, and itching, reported by the patient through a visual analog scale (VAS), from 0 (no discomfort) to 10 (maximum intensity).

Adverse events (AEs) were monitored throughout the clinical study. AEs were described as inappropriate medical events that were or were not associated with the procedures or the product.

The level of satisfaction with the investigational medical device was assessed using a scale ranging from 0 (none) to 10 (maximum satisfaction). Participants were asked two questions regarding their experience after using the lubricant: ‘Do you perceive any residue left by the lubricant in the vagina?’ and ‘Does the lubricant result in staining on your underwear?’ Responses were collected using a 5-point Likert scale, with options ranging from ‘None’ to ‘Much’.

Statistical analysis

A descriptive analysis was performed for all variables collected in the clinical investigation, stratified by visit. Continuous variables were described in terms of central tendency (mean and standard deviation), while categorical or ordinal variables were described using frequencies (n) and percentages (%).

For the primary effectiveness endpoint (the FSFI), the analysis involved examining the evolution of each domain and the full score. Mean comparisons between visits were conducted using paired t-tests. A similar approach was applied to assess the changes in the severity of VD symptoms based on the VAS data. Mean scores were compared using paired t-tests to analyze the progression between visits.

The safety analysis encompassed the safety population, and all reported AEs associated with the use of the investigational device were documented and presented. The safety analysis was primarily descriptive, and no statistical tests were applied in this evaluation.

The collected data were analyzed using the statistical software SAS®. (Statistical Analysis System) software, version 9.2 (SAS Institute, Inc., Cary, NC, USA).

Results

A cohort consisting of 55 patients was initially recruited for the study. One patient was excluded from the analysis due to noncompliance with the inclusion/exclusion criteria, specifically, the patient reported not having engaged in sexual intercourse. Consequently, the subsequent analysis was conducted on a cohort of 54 patients. A total of 51 patients successfully completed the study and were included in the safety analysis. For the comparison of baseline and third-month data on the FSFI, data from 42 participants were available and utilized for the analysis.

Demographic and clinical characteristics of study patients

The baseline report presents findings from a sample of 54 patients experiencing pain or difficulties during sexual intercourse, attributed to symptoms of VD. The age range of the women in the study varied from 19 to 72 years (mean 47.77 ± 11.6 years), with 41% classified as fertile and 59% as climacteric or postmenopausal.

At the baseline assessment, the mean score for the FSFI was 22.1 out of 36, ranging from 10.2 to 34.4 (Table 1). The domain associated with the lowest score was pain, with a mean of 2.8 ± 1.0, followed by desire, with a mean of 3.3 ± 1.3. The domain associated with the highest average score was satisfaction, with a mean of 4.5 ± 1.3.

Table 1. Baseline assessment of Female Sexual Function Index (FSFI), severity of vaginal dryness symptoms and hydration assessment.

Baseline assessment	Mean (SD)
Female Sexual Function Index (FSFI)^a
Full scale score, n = 52	22.1 (5.6)
Desire, n = 52	3.2 (1.3)
Arousal, n = 52	4.0 (1.3)
Lubrication, n = 52	3.3 (1.0)
Orgasm, n = 52	4.2 (1.3)
Satisfaction, n = 52	4.5 (1.3)
Pain, n = 52	2.8 (1.0)
Severity score of symptoms^b
Irritation, n = 53	4.91 (2.7)
Dryness, n = 54	6.50 (2.4)
Itching, n = 53	2.94 (2.4)
Dyspareunia, n = 54	6.53 (2.7)
Hydration assessment^c, n = 54	4.43 (2.5)

^aFSFI scored from 0 (no sexual activity) to 36. ^bVisual analogue scale (VAS) from 0 = no discomfort to 10 = maximum intensity. ^cVAS from 0 = not at all hydrated, not at all to 10 = maximum hydration and softness.

All patients reported experiencing one or more symptoms of VD (Table 1). 86.8% reported irritation, 98.1% reported dryness, 54.7% reported itching, and 92.5% reported dyspareunia. The severity of symptoms ranged from a mean of 2.9 ± 2.4 for itching to a mean of 6.5 ± 2.7 for dyspareunia.

Efficacy

The mean of frequency of use of the lubricant was 1.9 times a week. Following a three-month period of utilizing the vaginal lubricant, noteworthy increases were observed in the scores obtained from the FSFI (Table 2). Both the overall score (p < .001) and the individual domain scores demonstrated significant improvements (with significance ranging from p < .001 to p = .016). The domains related to pain and lubrication exhibited the most substantial score enhancements.

Table 2. Female Sexual Function Index (FFSI) after 3 months of treatment.

Female Sexual Function Index difference month 3 – baseline	Baseline mean (SD)	Month 3 mean (SD)	Difference mean (SD)	p-value
Full scale score, n = 42	21.7 (5.7)	25.8 (4.7)	4.1 (5.0)	.001
Desire, n = 42	3.1 (1.4)	3.6 (1.2)	0.5 (0.8)	.001
Arousal, n = 42	3.9 (1.3)	4.3 (1.0)	0.4 (0.9)	<.05
Lubrication, n = 42	3.3 (1.0)	4.1 (1.0)	0.8 (1.0)	<.001
Orgasm, n = 42	4.1 (1.3)	4.6 (0.9)	0.5 (1.0)	<.01
Satisfaction, n = 42	4.4 (1.2)	4.9 (1.0)	0.5 (1.4)	<.05
Pain, n = 42	2.9 (1.1)	4.2 (1.1)	1.4 (1.3)	<.001

The severity of symptoms associated with VD exhibited a significant reduction after 3 months of lubricant usage (Table 3). Specifically, there was an average decrease of −2.46 points for irritation, −3.5 points for dryness, −1.1 points for itching, and −3.8 points for dyspareunia, relative to the initial scores. Intimate hydration experienced a significantly increased mean of 2.0 points on the VAS (p < .001).

Table 3. Symptom severity score after 3 months of treatment.

Symptoms severity score difference month 3 – baseline	Baseline mean (SD)	Month 3 mean (SD)	Difference mean (SD)	p-value
Irritation, n = 48	5.00 (2.72)	2.54 (1.93)	−2.46 (2.59)	<.001
Dryness, n = 49	6.55 (2.42)	3.04 (2.10)	−3.51 (2.52)	<.001
Itching, n = 48	3.13 (2.45)	2.00 (1.80)	−1.13 (2.43)	<.01
Dyspareunia, n = 46	6.37 (2.61)	2.52 (1.83)	−3.85 2.60)	<.001

Patient experiences

Upon completion of a three-month period of using the vaginal lubricant, the mean (SD) satisfaction score was reported to be 8.0 (1.5) out of 10. Regarding postusage experiences, 52.9% of the patients reported minimal residual effects in the vaginal area, while 39.2% reported no residual effects. The incidence of staining on underwear was observed to be negligible for the majority of patients (64.0%), while a smaller proportion (30.0%) reported minimal staining (Figure 1).

Figure 1. Postuse experiences of patients.

Adverse events

Seven AE were reported, of which six were probable or possible relationship to the device, and in three cases, they led to the temporary interruption or regimen/dose reduction of vaginal lubricant. The AEs consisting in spotting and mild stinging/itching/irritation for few minutes at the time of application.

No serious AEs have been reported. No device deficiencies have been reported.

Discussion

The results of this clinical investigation demonstrated significant improvements in both the overall score and individual domain scores of the FSFI following a 3-month treatment with the vaginal lubricant. There was a marked reduction in symptoms associated with VD, including irritation, dryness, itching, and dyspareunia, as reflected by decreases in average scores. There was a notable increase in mean scores related to intimate hydration. Patient satisfaction with the vaginal lubricant was remarkably positive, with the majority of patients reporting minimal residual effects in the vaginal area. The incidence of staining on underwear was minimal for most patients. Among the reported AEs (totaling 7 cases), the severity was generally mild, and these events resolved spontaneously or with temporary interruption or dosage reduction of the treatment.

Further patient-reported outcomes (PROs), including FSFI [23–25], were employed to assess and measure the effectiveness of the investigated lubricant. PROs offer a comprehensive evaluation of the advantages and potential risks associated with novel medical products [26,27]. Therefore, the 12-item Female Sexual Distress Scale (FSDS) questionnaire was used, with a maximum score of 48. An FSDS score ≥15 corresponds to clinically significant distress [Derogatis LR, Rosen R, Leiblum S, Burnett A, Heiman J. The Female Sexual Distress Scale (FSDS): initial validation of a standardized scale for assessment of sexually related personal distress in women. J Sex Marital Ther. 2002 Jul-Sep;28(4):317-30. doi: 10.1080/00926230290001448. PMID: 12082670.]. In summary, women with an FSFI score of ≤26.55 are considered to have sexual dysfunction if they have an FSDS score ≥15. (Caruso S, Bruno MT, Boemi S, Palermo G, Mazza G, Caruso G. Vaginal health and quality of sexual life of postmenopausal women on hyaluronic acid and Biosaccharide Gum-1 vaginal gel. Taiwan J Obstet Gynecol. 2023 Sep;62(5):702-708. doi: 10.1016/j.tjog.2023.07.011. PMID: 37678998.)

The primary constituent of CLMG is HA, an essential mucopolysaccharide abundantly present in the extracellular matrix [22]. The findings of the present study are consistent with previous investigations who have examined the effectiveness of HA gels in the management of VD, dyspareunia, and atrophy [14,17,20,21,28–30]. Caruso et al. [31], in a nonrandomized comparative cohort study in postmenopausal women, showed that a vaginal gel containing HA and Biosaccharide Gum-1 (BG-1) produced a reduction in pain syndrome that could be due to the synergistic activity between the trophic effects of HA and the inhibition by BG-1 of the synthesis of inflammatory mediators and neurogenic inflammation. These treatment benefits were not observed in the control group. Furthermore, women reported more significant improvement in somatic than mental health aspects of quality of live. Most studies, except for the investigation conducted by Mieza Arana et al. [23], have primarily utilized populations consisting predominantly of post-menopausal women. Dyspareunia related to VD can also manifest in premenopausal women, albeit with lower prevalence rates. Terauchi et al. [32], conducted a study involving a cohort of 1702 Japanese women encompassing pre-, peri-, and postmenopausal stages, revealing that severe dyspareunia was experienced by 7.1%, 10.5%, and 14.6% of participants, respectively, highlighting the influence of hormonal status on this condition. Difficulties with arousal and lubrication can also be indicative of female sexual interest/arousal disorder [2,33]. Although no studies have directly compared the impact of dyspareunia related to VD on quality of life between pre- and postmenopausal populations, it is reasonable to anticipate that the younger group may experience a greater impact [34,35].

Only 3 previous studies have examined sexual well-being and pleasure as outcomes, of which, one of them focused only on postmenopausal women [12,36,37]. The present work is the only one to analyze these factors in a lubricant formulated with HA. The results from this investigation build on a limited evidence base and provide clinical evidence for the efficacy and safety of lubricants in relieving discomfort associated with VD, and their potential role in improving the sexual experience for women.

The findings from this study underscore a notable level of satisfaction among participants with regard to the utilization of the lubricant, coupled with minimal reported residue. These data support treatment adherence and encourage broader lubricant use, not just for managing VD but also for improving sexual intercourse.

The clinical implications of this study are to expand knowledge about the effectiveness of lubricants in improving vaginal dryness, since with the increase in life expectancy and the improvement of the functional health of women, the treatment of dyspareunia related to vaginal dryness still represent an unmet need.

This study possesses several limitations. Firstly, and the study design was an open-label, single-arm, multicenter, prospective investigation lacking a placebo control, thereby restricting the generalizability of the findings. While comparing results to the baseline state offers certain advantages [38], it is widely acknowledged that placebo-controlled comparisons are regarded as the gold standard in research [39]. Some of the PROs employed in this study were not based on validated questionnaires, which may introduce limitations in the interpretation of the data. It should also be noted that clinically significant discomfort due to dyspareunia related to VD was not assessed [40]. The absence of participant blinding potentially introduces bias into the study’s outcomes [41]. The small number of women evaluated is also a limitation. This study only examined the use of the product among women over a period of three months, leaving uncertainties regarding whether similar or improved outcomes would be observed with continued usage of the lubricants. There were no studies covering the effect of a lubricant in dyspareunia with longer follow-up times. Lastly, the findings of this study, conducted in Spain, may have limited generalizability to other populations. The characteristics of the healthcare system and demographic data of the study population may not be representative of broader populations, thus impeding the extrapolation of the results to other countries.

Conclusions

The Cumlaude Lab Mucus Gel® (CLMG) has shown significant efficacy in improving various aspects of female sexual function, including desire, satisfaction, and specifically addressing pain and lubrication issues during intercourse. It effectively reduces the intensity of VD symptoms such as irritation, itching, and dyspareunia. Participants using the product for three months reported positive evaluations and high levels of satisfaction. The product exhibited a favorable safety profile, with minimal and transient adverse events shortly after application and no reports of serious adverse events. In conclusion, this study provides evidence supporting the efficacy and safety of CLMG for treating dyspareunia related to VD and suggests its potential to normalize lubricant use, thereby enhancing sexual fitness and overall sexual health.

Statement of ethics

All patients provided written informed consent upon enrollment, signifying their voluntary participation in the study. The study protocol received approval from the independent ethics committee of the Grupo Hospitalario Quirónsalud-Catalunya at its meeting on April 04, 2022. This research adhered strictly to the principles delineated in the Helsinki Declaration and fully complied with the regulations stipulated in the EU General Data Protection Regulation (GDPR). In accordance with the guidelines outlined by the GDPR, stringent measures were implemented to ensure the proper anonymization and secure storage of all personal data, which were kept separate from the research results.

Authors’ contributions

RS-B: is one of the study designers, has participated in the elaboration and writing of the article and is the current corresponding author. MS-P: is one of the study designers, has carried out data collection and has participated on the conceptualization and writing of the manuscript and critical revision of it. The rest of the authors carried out the data collection and critical review of the manuscript. All authors read and approved the final manuscript.

Ethics approval and consent to participate

All patients provided written informed consent upon enrollment, signifying their voluntary participation in the study. The study protocol received approval from the independent ethics committee of the Grupo Hospitalario Quirónsalud-Catalunya at its meeting on April 04, 2022. This research adhered strictly to the principles delineated in the Helsinki Declaration and fully complied with the regulations stipulated in the EU General Data Protection Regulation (GDPR). In accordance with the guidelines outlined by the GDPR, stringent measures were implemented to ensure the proper anonymization and secure storage of all personal data, which were kept separate from the research results.

Disclosure statement

RS-B reports research funding from Astellas, Mitra, and Exeltis and personal fees from HR-Pharma, Seid, and Lacer, outside the submitted work. The rest of the authors declare no conflicts of interest.

Availability of data and materials

The datasets during and/or analyzed during the current study available from the corresponding author on reasonable request.