AH'S FLAGSHIP CLINICAL APPLICATIONS.
Aesthetic and functional health in gynecology and HA.
Les Entretiens de L&M: Interview with Pr Pierre MARES.

MULTI-POINT VAGINAL INJECTIONS OF CROSS-LINKED HYALURONIC ACID FOR THE TREATMENT OF MENOPAUSAL GENITOURINARY SYNDROME (MGUS) ASSOCIATED WITH VULVOVAGINAL ATROPHY (VVA).
Keywords: dryness, dyspareunia, hyaluronic acid, menopause, genitourinary syndrome, vulvo-vaginal atrophy.
Pr Albert Claude BENHAMOU (L&M)
In 2022, you published BMC WOMAN HEALTH (Berreni et al. BMC Women's Health 2021; 21: 322 https://doi.org/10.1186/s12905-021-01435-w) with Nicolas Berreni and your teams, Jennifer SALERNO, Thierry CHEVALIER, Sandrine ALONSO, and you, a text on the impact of multi-point vaginal injections of cross-linked hyaluronic acid for the treatment of vulvovaginal atrophy.
Why is this subject so important? Why is this subject insufficiently taken into account, particularly in the context of the genitourinary syndrome of the menopause and in the aftermath of chemotherapy and hormone therapy following breast cancer?
Pr Pierre MARES
This is a very common gynecological problem, with frequent but often unrecognized public health consequences. Why is this so?
It should be remembered that vulvovaginal atrophy (VVA) is one of the common consequences of estrogen deficiency, particularly after menopause [1, 2, 3, 4], and is associated with a number of clinical symptoms, including dryness, irritation, pruritus, dyspareunia and recurrent urinary tract infections, which can have a significant negative impact on a woman's quality of life [5].
Unawareness is linked to an onset that is often subtle and gradual, only becoming noticeable once other symptoms - such as hot flushes - of menopause have subsided.
The literature reports that up to 55 %, 41 % or 15 % of postmenopausal women suffer from vaginal dryness, dyspareunia and recurrent urinary tract infections respectively [6, 7, 8, 9].
We believe that the real prevalence of these problems is higher, as a majority of women, due to lack of information or embarrassment about exposing their intimate and sexual lives, do not seek medical help [6].
Pr Albert Claude BENHAMOU
Can you remind L&M readers of the mainstays of the management of MGS and VTA, and of the new therapeutic perspectives?
Pr Pierre MARES
The mainstay of VVA management is listening and providing information, so that the right treatment can be offered. Treatments combine lifestyle modifications, non-hormonal treatment options (e.g. vaginal lubricants or moisturizers), physical treatments: laser/radiofrequency/photobiomodulation = PBM = LED and hormonal.
Vaginal lubricants are mainly used to relieve vaginal dryness during intercourse, and are therefore a first-level solution for VVA symptoms.
On the other hand, vaginal moisturizers are "bio-adhesive" products that facilitate water retention to improve vaginal irritation and dyspareunia when used regularly [10]. Nevertheless, this is not associated with an improvement in the overall maturation index of the vaginal epithelium [11].
In recent years, a number of allegations have been made concerning the use of radiofrequency and lasers for the treatment of vaginal menopausal symptoms [12, 13, 14, 15]. Nevertheless, the FDA has issued a patient alert pointing out that the use of such procedures could be associated with serious adverse events, and that the safety and efficacy of energy-based devices for the treatment of these conditions has not been established [16].
Photobiomodulation (PBM / Led) has also taken pride of place in these therapeutic proposals.
Evidence from meta-analyses of several randomized studies supports the effectiveness of both local and systematic hormone treatmentsto relieve symptoms associated with VTA [17, 18, 19].
However, a limited number of studies have assessed the lasting effect of such treatments beyond 6 months. What's more, contraindications and personal choices in the current period are sometimes limiting factors to widespread, long-term use.
As a result, there is currently a demand for a multimodal solution combining these different therapies, which include a local background treatment and a booster treatment such as laser, radiofrequency, or PBM/LED for MGS and VMA.
Pr Albert Claude BENHAMOU
You mentioned the role of physical treatments using high-frequency ultrasound and/or lasers as possible contributors. What is the actual situation?
Pr Pierre MARES
In recent years, a number of allegations have been made concerning the use of radiofrequency and lasers for the treatment of vaginal menopausal symptoms [12, 13, 14, 15].
Nevertheless, the FDA has issued a warning to patients that the use of such procedures could be associated with serious adverse events when users fail to follow industry recommendations [16].
Pr Albert Claude BENHAMOU
Does this explain why you consider research into intravaginal hyaluronic acid to be so important?
On what rational basis can this be demonstrated and implemented in gynecological practice on a wider scale in the near future?
What are the new therapeutic prospects? Does hyaluronic acid have a place in this research?
Pr Pierre MARES
Research into intra-vaginal hyaluronic acid injection is rich and promising. There are many answers to your questions.
1/ The rational basis for the use ofhyaluronic acid (HA) are very important: HA is a key extracellular matrix molecule present in many tissues, including the vaginal mucosa.
It is a polysaccharide of the glycosaminoglycan family that plays a major role in maintaining water balance, regulating inflammation, immune response, scarring and angiogenesis [20, 21].
2/ HA preparations are available as local gels. They have "medical device" status.
Several studies have evaluated the effects of HA on physical and sexual symptoms associated with VVA with promising results [22, 23, 24, 25]. However, most of these studies have focused on subjective assessment of symptom response to topical treatments.
3/ Since HA is an endogenous molecule, it is logical that its effects are more effective if it is injected into the superficial epithelial layers of the vagina.
Desirial® is the first cross-linked HA administered by injection into the vaginal mucosa.
Several studies have evaluated the effects of hyaluronic acid (HA) on the physical and sexual symptoms associated with MGS and VVA, with promising results.
However, most of these studies have focused on subjective assessment of symptomatic response to topically administered preparations.
Pr Albert Claude BENHAMOU
What was the aim of your study published in the BMJ WH?
Pr Pierre MARES
The aim of this study was to explore the effect of multi-point vaginal intramucosal injections of specific cross-linked hyaluronic acid (Desirial®Laboratoires VIVACY) on several clinical parameters observed by patients.
A pilot bicentric cohort study was defined.
Here are the basics: 8 weeks after Desirial injection® results were to include analysis of several parameters:
- changes in the thickness of the vaginal mucosa;
- biological markers of collagen formation ;
- vaginal flora;
- vaginal pH ;
- vaginal health index;
- symptoms of vulvovaginal atrophy;
- and sexual function;
- Patient satisfaction was also assessed using the Patient Global Impression of Improvement (PGI-I) scale.
Several patient-reported outcomes were evaluated, including changes in sexual function and incidence of VVA-related symptoms over the same period, and patient satisfaction using the Global Impression of Improvement (GII-I) scale at the end of the study.
The study population consisted of post-menopausal women (between 2 and 10 years post-menopause) followed at the Menopause Clinic, presenting with symptoms of vaginal discomfort, and/or secondary dyspareunia, and/or vaginal dryness.
Women were aged ≥ 18 years and < 70 years with a BMI < 35. Reticulated HA (Desirial®) was injected by one of the 2 trained specialists following the standard protocol.
Desirial® [IPN-Like 19 mg/g cross-linked NaHa (sodium hyaluronate) + Mannitol (antioxidant)] is a single-use, injectable HA gel packaged in pre-filled syringes (2 × 1 mL).
This is a class III medical device (CE 0499) intended for intramucosal injection in women for biostimulation and rehydration of the superficial mucosal layers of the genital area.
A dozen injections of 70 to 100 μl each (0.5 to 1 mL in total) were performed in 3 to 4 horizontal lines over a triangular area of the posterior vaginal wall with its base at the level of the fork and the apex 2 cm above.
Pr Albert Claude BENHAMOU
What were the results of your preliminary study?
Pr Pierre MARES
A total of 20 participants were recruited between 19/06/2017 and 05/07/2018. At the end of the study, there was no difference in median total vaginal mucosal thickness or in procollagen I, III or Ki67 fluorescence.
However, there was a statistically significant increase in the expression of the COL1A1 and COL3A1 genes (p = 0.0002 and p = 0.0010 respectively). which are collagen precursors.
There was also a significant reduction in dyspareunia, vaginal dryness, vulvar pruritus, vaginal irritation and a significant improvement in IHV.
Based on the PGI-I, 19 patients (95 %) reported varying degrees of improvement, with 4 (20 %) feeling slightly better; 7 (35 %) better and 8 (40 %) much better.
Pr Albert Claude BENHAMOU
What comments can we make based on this work?
Pr Pierre MARES
The hypothesis underlying this study was that multi-point injections of Desirial®In the posterior vaginal wall, they thicken the vaginal mucosa, lower vaginal pH, improve vaginal flora, induce collagen formation and improve VVA symptomatology.
The beneficial effects of HA have been evaluated in several studies, most of which were non-inferiority RCTs comparing HA with other, mainly hormonal, forms of treatment [22, 23, 24, 25]. HA in these studies was administered topically.
HA is an endogenous molecule with an extremely important capacity to bind and transport water. With age, the amount of endogenous HA in the vaginal mucosa diminishes sharply, as do its thickness and vascularization, thus reducing transudation and lubrication.
In this study, we demonstrated that injections of Desirial® were associated with a significant improvement in all symptoms associated with stroke.
Other studies have also shown that cross-linked HA gel increases the synthesis of type I collagen and elastin, and thus the thickness of surrounding tissue [31, 32].
In our study, we showed no significant difference in procollagen I and III fluorescence after treatment. Nevertheless, there was a statistically significant increase in COL1A1 and COL3A1 gene expression.
Consequently, it is possible that Desirial® may have a stimulating effect on collagen formation in the vagina and by stimulating aquaporins.
However, larger studies with longer follow-up will be needed to confirm or refute this possibility.
Consequently, it is imperative that additional histological and biological markers are explored in future studies.
Pr Albert Claude BENHAMOU
What conclusions can be drawn from this preliminary work?
Pr Pierre MARES
Desirial multi-point vaginal injections® are significantly associated with CoL1A1 and CoL3A1 expression, suggesting stimulation of collagen formation, and a significant reduction in VTA symptomatology.
In addition, there was a significant improvement in patient satisfaction and sexual function based on PGI-I and FSFI scores respectively.
However, no demonstrable change was observed in the total thickness of the vaginal mucosa.
All this confirms the importance of managing these symptoms as early as possible, and the effectiveness of available therapeutic combinations: local treatments, physical techniques using Laser, Radiofrequency, or PBM (Photo Bio Modulation) with hyaluronic acid applied locally or injected.
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